Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[NH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=4)=[O:14])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:37]=[CH:38][C:39]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]4)=[O:25])=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:13]([N:10]2[CH2:9][CH2:8][N:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:5])=[O:6])[CH2:12][CH2:11]2)=[O:14])=[CH:40][CH:41]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C4CC4)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-cyclopropanesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 33) and 2-chloropyridine-5-boronic acid to afford the desired product as light brown foam (44%). MS (ISP): 599.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:27]4[CH:28]=[CH:29][C:24]([C:22]([NH:21][CH3:20])=[O:23])=[CH:25][CH:26]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Yield: 68.7 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.300 g, 0.777 mmol) and 4-(methylcarbamoyl)phenylboronic acid (0.174 g, 0.971 mmol) according to the procedure described for Example 94, Step A. Purified by trituration from hot MeOH to obtain the product (210 mg, 96%) as a brown solid. LRMS (APCI pos) m/e 394 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([C:23]#[N:24])=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(CN)s3)cc(C)c21
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of [6-(5-cyano-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.41 g, 1.14 mmol) in ethanol (10 mL) was added 10% Pd/C (0.036 g, 0.34 mmol) and the suspension was hydrogenated at 50 psi for 3 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give [6-(5-aminomethyl-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.22 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H), 8.69 (br. s., 3H), 7.51 (d, J=2.26 Hz, 1H), 7.34 (d, J=1.94 Hz, 1H), 5.58 (dd, J=8.92, 2.55 Hz, 1H), 4.41 (s, 2H), 4.05 (q, J=7.14 Hz, 2H), 3.16 (dd, J=16.72, 1.75 Hz, 1H), 2.35-2.42 (m, 1H), 2.35 (s, 3H), 1.14 (t, J=7.15 Hz, 3H).
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C1C=CC=CC=1)(C1C=CC=CC=1)[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:19]3[C:20](=[O:34])[NH:21][C:22](=[O:33])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[C:16]([CH3:18])[N:17]=2)[CH:14]=1)(C)(C)C>>[OH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:19]3[C:20](=[O:34])[NH:21][C:22](=[O:33])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[C:16]([CH3:18])[N:17]=2)[CH:14]=1
Reactant: Cc1nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Agent: Cl
Product: Cc1nc2ccc(CO)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 45 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A 4 M aqueous solution of hydrochloric acid (5.0 ml) is added to 3-[6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-4-(1H-indol-3-yl)-pyrrole-2,5-dione (180 mg, 0.29 mmol). The reaction mixture is stirred for 24 hours at 45° C. After removal of volatiles in vacuo, purification via flash chromatography (CH2Cl2/MeOH 95:5) affords the title compound (90 mg, 82%). 1H NMR (400 MHz, d6-DMSO): δ=11.94 (s, 1H), 11.08 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.13 (dd, J=9.0/1.8 Hz, 1H), 6.92 (dt, J=7.8/1.0 Hz, 1H), 6.46 (dt, J=7.6/1.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 1H), 5.14 (t, J=5.4 Hz, 1H), 4.25 (t, J=4.7 Hz, 2H), 1.84 (s, 3H). (ES+): 373 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]#[CH:3].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[H-].[Na+]>C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]=[CH:17][CH2:16][C:4]([CH2:1][C:2]#[CH:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Clc1ccccc1/C=C/CBr
Reactant: C#CCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCC(CC=Cc1ccccc1Cl)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
An oven-dried, 100 mL three-necked round-bottomed flask under a nitrogen atmosphere was charged with diethyl 2-(prop-2-yn-1-yl)malonate S13 (1.8 g, 9.1 mmol), (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene S14 (2.1 g, 11.0 mmol), and THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15 min, then NaH (0.43 g of a 60% dispersion in mineral oil, 11.0 mmol) was added in one portion. The solution was stirred at 0° C. for 2 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 0.5:9.5). The reaction was then quenched with sat'd aq ammonium chloride solution (70 mL). The layers were separated and the aqueous phase was extracted with AcOEt (3×50 mL). The combined organic layers were dried over Na2SO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 2.55 g of the title compound as a yellow oil in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH2:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH-].[Li+:28].Cl>C1COCC1.CCO.O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23])[CH2:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13].[Li+:28]
Reactant: CCOC(=O)CCCC1CN(CC(=O)OC(C)(C)C)c2cccc(N)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CC(CCCC(=O)[O-])c2c(N)cccc21
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoate from Step D (1.00 g, 2.76 mmol) in THF (30 mL), EtOH (15 mL) and H2O (15 mL) was added 1.0 N lithium hydroxide (2.76 mL, 2.76 mmol). After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7 and the mixture was concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=335 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1.SCCO>FC(F)(F)C(O)=O.C(OCC)(=O)C>[SH:14][C@@H:12]1[CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[C@H:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:13]1
Reactant: CN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: OCCS
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of (2S,4S)-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.85 g) in trifluoroacetic acid (35 ml) was added 2-mercaptoethanol (1.13 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in toluene (40 ml) and the solution was evaporated in vacuo to give a syrup. The syrup was dissolved in ethyl acetate (100 ml) and washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (10:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.14 g).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH2:24][CH2:25][F:26])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH2:24][CH2:25][F:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCCCF)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCCCF)C1
Yield: 105.2 %

Procedure:
The same operation as in Example (95d) was performed using tert-butyl cis(±)-4-(benzylamino)-3-(3-fluoropropoxy)piperidine-1-carboxylate obtained in Example (127c) (1.06 g, 2.89 mmol), 10% Pd/C (wet, 0.4 g), ammonium formate (1.09 g, 17.4 mmol) and methanol (15 mL), to obtain 0.84 g of the title compound as a colorless oily substance (100%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45](=[O:55])[CH:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=1>CN(C)C=O.CO>[CH3:43][O:44][C:45](=[O:55])[CH:46]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=1)[N:25]1[CH2:24][CH2:23][N:22]([C:20](=[O:21])[NH:19][C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([O:9][CH3:8])[C:11]=3[N:18]=2)[CH2:27][CH2:26]1
Reactant: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Reactant: COC(=O)C(Br)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C(c1cccc(Cl)c1)N1CCN(C(=O)Nc2nc3c(OC)ncnc3s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of Piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide trifluoroacetate salt (1.56 g, 3.82 mmol), diisopropylethylamine (2.7 mL, 15.5 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 30 minutes. To the mixture was added potassium carbonate (0.8 g, 5.8 mmole) and Bromo-(3-chloro-phenyl)-acetic acid methyl ester (1.0 g, 3.8 mmol) and the resulting mixture was stirred at room temperature overnight. Filtration and concentration gave a solid which was dissolved in methanol and absorbed onto 2 g of silica gel. The silica gel was loaded onto an Isco 120 g column and eluted using 0→5% Methanol/methylene chloride to yield (3-Chloro-phenyl)-[4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazin-1-yl]-acetic acid methyl ester as a white powder; LRMS for C20H21ClN6O4S (M+H)+ at m/z=477. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[F:21][C:22]1[CH:27]=[C:26]([CH:28]=[CH:29][C:30]#[N:31])[CH:25]=[CH:24][N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:28]2[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:25]=[CH:24][N:23]=1
Reactant: N#CC=Cc1ccnc(F)c1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2ccnc(F)c2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 296 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(2-fluoro-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:15]([CH2:19][C:20](=O)[CH3:21])[C:16]([CH3:18])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:21][C:20]1[CH:19]=[CH:15][C:16]([CH3:18])=[C:2]2[C:3]=1[C:4]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=1[NH:1]2
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1cccc2[nH]ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc2[nH]c3c(C)ccc(C)c3c12
Yield: 39.8 %

Procedure:
A mixture of 13.24 g of ethyl indole-4-carboxylate, 15.98 g of acetonylacetone and 13.31 g of p-toluenesulfonic acid monohydrate in 50 ml of ethanol was refluxed for 10 hours. The ethanol was evaporated under reduced pressure, the residue was chromatographed on silica gel column with hexane - ethyl acetate (9 : 1) to give 7.45 g of ethyl 5,8-dimethylcarbazole-4-carboxylate.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=O)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOCc1cccc(Cn2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17](Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].C1(=O)CCCCC1>>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH3:18]
Reactant: CC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCOc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reaction time: 6 h

Procedure:
A reaction vessel was charged with 230 g of 4-hydroxy-4'-acetylbiphenyl, 164 g of ethyl bromide, 276 g of potassium carbonate and 1.7 l of cyclohexanone. The mixture was reacted together under agitation for 3 hours at 65°-70° C. and then for 6 hours at 95°-100° C. The reaction liquid was filtered and the resultant solid matter was washed with benzene. The filtrate and the washing liquid were combined, washed with water and dried over Glauber's salt, The solvents were distilled off and the residue was recrystallized from a mixed solvent of acetone-methanol to obtain 4-ethoxy-4'-acetylbiphenyl.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[C:22]([CH3:29])[CH:21]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[C:22]([CH3:29])[CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Cc1cc(N)ccc1CC#N
Agent: Cl
Product: Cc1cc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)ccc1CC#N
Yield: 46.5 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-amino-2-methylphenyl)acetonitrile (0.073 g, 0.50 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.063 g, 63%) as a white solid. MW=410.34. 1H NMR (DMSO-d6, 500 MHz) δ 13.96 (s, 1H), 9.71 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.78-7.69 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 4.03 (s, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.34 (s, 3H), 2.28-2.19 (m, 2H); APCI MS m/z 374 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:27](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[CH:11]=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[N:13]=[CH:14][C:15]=4[N:16]=[CH:27]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cn1)c1ccc(F)cc1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc2c(cn1)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,4,5-triamine (Method 88, 0.15 g, 0.43 mmol) and formamidine acetate (0.089 g, 0.85 mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=40:1) to give the title compound as an off-white solid (0.092 g, 60%). 1H NMR (400 MHz) 12.75 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.42 (m, 2H), 7.08 (m, 2H), 6.90 (s, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.26 (d, J=1.6 Hz, 1H), 5.00 (m, 1H), 1.96 (m, 1H), 1.42 (d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 362; Found: [M+H]+ 363.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].S(Cl)(Cl)(=O)=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]=[N+:14]=[N-:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 30 °C
Yield: 96 %

Procedure:
274 g (1.33 mole) of p-methoxybenzenesulfonyl chloride was dissolved in one liter ethanol in a two liter Erlenmeyer flask. The solution was stirred magnetically and warmed to 30° C. 112 g (1.72 mole) of sodium azide was dissolved in a minimum amount of water and the sodium azide solution was then added to the sulfonyl chloride solution. Sodium chloride precipitated over a 30 minute period. The reaction solution was then poured into a 4 liter Erlenmeyer flask containing 2 liters of ice water. The resultant white solid was removed by filtration and air dried in a vacuum oven overnight at room temperature; yield 281 g of p-methoxybenzenesulfonyl azide (99% of theory; mp 39°-42° C.). The sample was crystallized from methanol to yield a white solid in 96% yield, mp 48°-50° C., lit. value mp 52° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[NH:7]1)[CH3:2].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[N:26][OH:27])[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reaction time: 0.08 h

Procedure:
The crude 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester obtained by reduction of 10 g. of the end produce of Example 15 as described above was dissolved in 40 ml. of glacial acetic acid. Sodium nitrite, 2.45 g., was added with stirring over a period of 5 minutes. Following the addition the mixture was stirred at room temperature for 15 minutes. The product started to crystallize and was further precipitated by addition of 50 ml. of water. The crystals were collected, washed with water, ethanol and ether to yield the end product. The analytical sample was recrystallized from tetrahydrofuran/ethanol to give pale yellow crystals with mp 230-°233°.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]2)[C:4]1=[O:24].[CH2:25]([N:32]1[CH2:37][CH2:36][O:35][CH:34]([CH2:38]Cl)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+]>CN(C)C=O>[CH2:25]([N:32]1[CH2:37][CH2:36][O:35][CH:34]([CH2:38][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([C:23]4[C:14](=[CH:15][C:16]5[O:21][CH2:20][CH2:19][O:18][C:17]=5[CH:22]=4)[O:13][CH2:12]3)[C:4]2=[O:24])[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(CC2CN(Cc3ccccc3)CCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 0.48 g, 12 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (2.95 g, 10 mmol). The reaction mixture was stirred for 30 min and 4-benzyl-2-(chloromethyl)morpholine (2.71 g, 12 mmol) and potassium iodide (0.10 g, 0.60 mmol) were added. The reaction mixture was heated at 100° C. for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (3/7) to afford 1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.75 g, 74%) as a colorless solid: mp 88-100° C.; 1H NMR (mixture of diasteroisomers, 300 MHz, CDCl3) δ7.35-7.20 (m, 6H), 7.16-7.11 (m, 1H), 7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.25 (s, 0.5H), 6.20 (s, 0.5H), 4.90-4.80 (m, 1H), 4.64-4.57 (m, 1H), 4.22-4.08 (m, 4H), 3.98-3.40 (m, 7H), 2.87-2.56 (m, 2H), 2.23-1.98 (m, 2H); MS (ES+) m/z 485.0 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C(Cl)Cl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:19]=[C:15]1[C:14]2[C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12][C:13]=2[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3

Procedure:
A mixture of methyl 2-bromo-3-(3-oxocyclohex-1-enylamino)benzoate (0.97 g, 3.0 mmol), palladium acetate (0.14 g, 0.6 mmol), tri-o-tolylphosphine (0.73 g, 2.4 mmol), and triethylamine (0.38 g, 3.6 mmol) in acetonitrile (10 mL) was heated in a sealed tubule flushed with nitrogen at 100° C. for 20 h. The cooled reaction mixture was diluted with DCM (3×50 mL) and water (10 mL). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated.