Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])/[C:15]/3=[CH:22]\[C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O.O.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])/[C:15]/3=[CH:22]\[C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc([N+](=O)[O-])cc3)cc2/C1=C/c1ccc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C#Cc2ccc3c(c2)/C(=C/c2ccc[nH]2)C(=O)N3)cc1

Procedure:
To a solution of (Z)-1,3-dihydro-5-(4-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (45 mg, 0.13 mmol) (from Example 89) in 1 mL of a 10% water in methanol solution and 0.5 mL THF was added zinc dust (145 mg, 2.21 0 mmol) followed by ammonium chloride (25 mg, 0.47 mmol). The reaction was heated at gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® (Fisher Scientific) and rinsed thoroughly with ethyl acetate. The resulting solution was diluted with 5 mL water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc/hex to give (Z)-5-(4-aminophenyl)ethynyl-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 24 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:7]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1F
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzoyl chloride (27.0 g, 114 mmol) and anisole (12.9 g, 13.0 mL, 119 mmol) in dichloromethane (150 mL) at 0° C. was added aluminum trichloride (16.2 g, 119 mmol) portionwise so that the internal temperature remained below 10° C. After stirring for 4 hours at 0° C., the solution was poured over crushed ice and the resulting mixture was stirred. After 30 minutes, the organic phase was removed and the aqueous phase was extracted two times with dichloromethane. The combined organic phases were washed once with aqueous 1M hydrochloric acid solution, once with aqueous 1M sodium hydroxide solution, and once with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from ethanol to afford (5-bromo-2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone (22.5 g, 64%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=CC(C(OC)=O)=CC=1.[S:31]1C=CC=[C:32]1CCO>>[S:31]1[CH:32]=[CH:2][CH:3]=[C:1]1[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: OCCc1cccs1
Agent: COC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2cccs2)cc1
Yield: 65 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (1.55 g, 10.2 mmol) and 2-(2-thienyl)ethanol (1.20 mL, 10.8 mmol) to give 2.02 g of the title compound (white powder, yield: 65%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:12][CH2:13][C:14](=S)[NH:15][C:9]=2[CH:8]=[C:7]([Br:24])[CH:6]=1)(=[O:4])=[O:3].[OH:25][CH2:26][C:27]([NH:29][NH2:30])=O>C(O)CCC>[CH3:1][S:2]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:12][CH2:13][C:14]3[N:15]([C:27]([CH2:26][OH:25])=[N:29][N:30]=3)[C:9]=2[CH:8]=[C:7]([Br:24])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(Br)cc2c1C(c1cccc(F)c1)=NCC(=S)N2
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: CS(=O)(=O)c1cc(Br)cc2c1C(c1cccc(F)c1)=NCc1nnc(CO)n1-2

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-6-(methylsulfonyl)-8-bromo-5-(m-fluorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol was refluxed to give 7-(methylsulfonyl)-9-bromo-1-(hydroxymethyl)-6-(m-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[N:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, a solution of methyl 5-bromo-1H-indazole-7-carboxylate (as prepared according to WO2008/65508) (658 mg) in DMF (20 mL) was stirred under ice-cooling. 60% Sodium hydride (124 mg) was added slowly, and the mixture was stirred for 30 minutes at the same temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (544 μL) was added dropwise slowly using a syringe, and the mixture was stirred at room temperature for 4 hours. The mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (696 mg) as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred solution consisting of 7.03 g (5.0 mmol) of 4-chlorobenzaldehyde, 9.58 g (5.0 mmol) of 4-chlorobenzenesulfonamide, 8 g of 4A molecular sieves and 0.1 g of Amberlite IR-120 in 90 mL of toluene was heated to reflux. The reaction vessel was fitted with a Dean Stark trap which was filled with 4A molecular sieves. The mixture was heated for 4 hours, at which point TLC analysis showed conversion to sulfonimine. The mixture was allowed to cool to room temperature and was filtered. Concentration of the filtrate and subsequent recrystallization of the crude product from CHCl3 - hexane gave 7.84 g (50%) of sulfonimine as a white crystalline material: IR 3090, 1598, 1582, 1553, 1321, 1084 cm-1 ; 1H NMR (CDCl3, TMS, 60 MHz) & 9.02 (s, 1), 7.73 (A2B2, 4, Δν=24 Hz, JAB =8 Hz), 7.67 (A2 B2, 4,Δν=23 Hz, JAB =9 Hz); m p. 128.0 ° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29][N:30]1N=NC2C=CC=N[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13](=[O:15])[N:30]([O:29][CH3:25])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](C(=O)O)C1CCCCC1)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (25 g, 88 mmol) in DMF (100 mL) at −10° C. was added HATU (36.7 g, 96 mmol, 1.0 equiv) followed by N,O-dimethyl hydroxyamine HCl salt (10.3 g, 105 mmol, 1.2 equiv). To this solution was then slowly added N-methyl morpholine (28.9 mL, 263 mmol, 3.0 equiv). The internal temperature was carefully monitored. During the addition, the internal temperature rose to 0° C. The solution was stirred at 0° C. for 2 hours after which the solution was diluted with EtOAc (500 mL) and washed with sat. aq. NaHCO3 solution, water, 1.0 N aq. HCl solution and brine. The organic layer was dried over Na2SO4 and the solvent including DMF was removed under vacuum. The residue was diluted with EtOAc and the solution was washed with water, brine, dried (MgSO4) and concentrated to give product [(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzyl ester 26 g (yield 90%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([CH2:30][NH2:31])C[CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH2:30][C:27]#[CH:28])=[O:24])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NCC1CC1
Product: C#CCNC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 13 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using prop-2-ynlamine instead of cyclopropylmethylamine, to the title compound (15 mg, 13%) which was obtained as an off-white solid. MS: m/e=382.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH3:12]>CO>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
2,6-Dichloro-3-nitropyridine was suspended in MeOH, and the mixture was treated with ammonia at room temperature for 12 hours to yield 2-amino-3-nitro-6-chloropyridine. This was then treated with an ethanolic:aqueous solution of sodium hydroxide (10 M) at reflux to give 2-amino-3-nitro-6-(1H)-pyridinone. This was then treated with N-iodosuccinimide (1.05 equivalents) in dimethylformamide at room temperature to yield 2-amino-3-nitro-5-iodo-6-(1H)-pyridinone.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:17])[CH:2]=[CH2:3].O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:10]1[C:11]([F:13])=[CH:12][C:7]2[S:6][C:5](=[O:17])[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]=2[CH:9]=1
Reactant: C=CCn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1c(=O)sc2cc(F)c(N)cc21
Temperature: 80 °C
Yield: 97.2 %

Procedure:
A suspension of iron powder (0.77 g) in 5% aqueous acetic acid (1.5 ml) was heated at 80° C., and a solution of 3-allyl-6-fluoro-5-nitro-2(3H)-benzothiazolone (0.70 g) in acetic acid (2.8 ml) and ethyl acetate (2.8 ml) was added thereto, followed by heating under reflux at 60° to 80° C. for 3 hours. After cooling, water and ethyl acetate were added to the resultant mixture, followed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 5-amino-3-allyl-6-fluoro-2(3H)-benzothiazolone (0.60 g). nD26.0 1.6236.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:19][C:17](=[O:18])[C:16]2[CH:36]=[CH:37][C:38]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)=[CH:39][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:27])=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1ccncc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCNCC1
Yield: 89 %

Procedure:
The 3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-4-carboxamide (109 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL) with anisole (1 mL). The solution was treated with trifluoroacetic acid (1 mL) at room temperature for 2 h. The mixture was concentrated to dryness under vacuum, rinsed with hexanes, and sonicated with diethyl ether (5 mL) for 5 min to give 120 mg (0.16 mmol, 89%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12]CC(=O)C(OCC)=O.NC(N)=S.O1C=CN=C1.BrBr.C(=O)([O-])[O-].[Na+].[Na+]>Br>[NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CCOC(=O)C(=O)CBr
Agent: Br
Agent: BrBr
Agent: NC(N)=S
Product: CCOC(=O)c1nc(N)sc1Br
Temperature: 60 °C

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (5.0 g) (prepared from ethyl bromopyruvate and thiourea by the procedure described in J. Med. Chem., 1971, 14, 1075 for the corresponding oxazole) in concentrated hydrobromic acid (9 cm3) was stirred at ambient temperature and treated dropwise with bromine (3.2 g), then heated to 60° C. for 2 hours, neutralised with sodium carbonate and the product extracted into ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give ethyl 2-amino-5-bromothiazole-4-carboxylate (1.54 g). MH+ =251; 1H NMR: δ 1.40(3H,t); 4.40(21H,t); 5.6(2H,br s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12](OS(C)(=O)=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12]([S:35][C:33](=[O:36])[CH3:34])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (3S,5S)-methanesulfonic acid 5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester (3.0 g) in abs DMF (60 ml) was added potassium thioacetate (1.08 g). The reaction mixture was stirred for 1 h at 100° C. and concentrated under oil pump vacuum. The residue was treated with ice/water and extracted with EtOAc. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 as eluent to obtain (3S,5R)-thioacetic acid S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl] ester (2.16 g) as a slightly yellow powder, MS: 334 (M-121).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[N:19]=3)=[CH:17][C:12]2=[C:11]2[N:28]([CH3:31])[CH:29]=[N:30][C:10]=12)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:31][N:28]1[C:11]2=[C:12]3[CH:17]=[C:16]([C:18]4[N:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=4)[NH:15][C:13]3=[N:14][C:9]([NH:7][CH3:6])=[C:10]2[N:30]=[CH:29]1
Reactant: CC(=O)Nc1cccc(-c2cc3c(nc(N(C)C(=O)OC(C)(C)C)c4ncn(C)c43)[nH]2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc2[nH]c(-c3cccc(NC(C)=O)n3)cc2c2c1ncn2C
Reaction time: 0.25 h

Procedure:
A436.2 (55 mg, 0.13 mmol), was dissolved in DMA (5 mL) and the solution heated to 70° C. One equivalent of 1.0M potassium t-butoxide in THF (0.14 ml, 0.14 mmol) was quickly added and the reaction heated at 70° C. for thirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF (0.14 ml, 0.14 mmol) was quickly added and the reaction mixture stirred an additional thirty minutes. The reaction mixture was concentrated in vacuo. The crude product residue was chromatographed on Silica Gel (230-400 Mesh) eluting with 2-5% MeOH/CH2Cl2 to give the Boc-protected intermediate, tert-butyl-7-(6-acetamidopyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamate as an off-white solid. (26 mg, 60% yield). The solid was dissolved in methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction mixture stirred for 0.25 h. The solvent was evaporated under reduced pressure to provide A436 (20 mg, 60%). M+H+=336.34 1H NMR (400 MHz) MEOD δ 9.20 (s, 1H), 8.02 (m, 1H), 7.78 (m, 1H), 7.71 (d, 1H), 7.56 (s, 1H), 4.33 (s, 3H), 3.45 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH:5]=[C:6]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(C(C)=O)C>[F:21][C:15]1[CH:14]=[C:13]2[C:18](=[C:17]([F:19])[C:16]=1[F:20])[N:4]([CH2:3][CH2:2][F:1])[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]2=[O:23]
Reactant: CCOC(=O)C(=CNCCF)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
1.0 g of ethyl 3-(2-fluoroethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was dissolved in 8 ml of methyl ethyl ketone under heating to 75˜80° C. 1.14 g (1.8 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 1.5 hours. The reaction mixture was filtered under a reduced pressure and washed with 40 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 20 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 0.91 g of ethyl 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (Yield: 96.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC(Cl)C.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:34])=[N:31][C:32]=1[CH3:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:26][C:27]2[C:32]([CH3:33])=[N:31][C:30]([Br:34])=[CH:29][CH:28]=2)[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1nc(Br)ccc1N
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCNc2ccc(Br)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.56 g, 1.87 mmol) in 1-2 dichloroethane (DCE, 6 mL) was added 5-amino-2-bromo-6-picoline (0.35 g, 1.87 mmol), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 equiv.) was then added in one portion and the reaction mixture was allowed to stir at room temperature for 16 hours. The reaction was diluted with DCM (10 mL), quenched with 2 M of NH4OH in water (1 mL). The layers were separated, and the aqueous layer was extracted with DCM (10 mL, 2×). The combined organic layers were washed with aqueous NaHCO3 (10 mL), brine (20 mL), dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with ethyl acetate in heptanes (0-75%) afforded 0.44 g (50%) of title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH:36]3[CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CC2)no1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclopropylamine (210 μl, 2.96 mmol) as starting materials.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH:7](C(OC)=O)[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl>CS(C)=O.O>[I:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CC(=O)Nc2cc(I)ccc2C1=O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCC(=O)c2ccc(I)cc2N1
Temperature: 150 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
A mixture of methyl 8-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (74 g, 0.2 mol) in DMSO (560 mL) and H2O (16 mL) was heated at 150° C. for 4 h. The reaction mixture was allowed to cool to rt, ice (1.0 L) was added, and the mixture was allowed to stir 12 h. To the flask was added 1N HCl (1.0 L) at 0° C. and the mixture allowed to stir for 3 h. The resulting precipitate was filtered and dried under reduced pressure to afford 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (60 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](OC)[C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[CH:12][N:11]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: COC(c1ccc(CNc2ccc(Cl)cc2)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: Clc1ccc(NCc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1

Procedure:
To (4-Chloro-phenyl)-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-ylmethyl-amine (57, 20.8 mg, 0.055 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (1.00 mL, 6.26 mmol). The reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0078, 6.1 mg, 32.0%). MS (ESI) [M+H+]+=349.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[O:3]1.[CH2:19](Br)[CH3:20]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]#[N:17])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: CCBr
Product: CCC(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 59.7 %

Procedure:
Following the procedure outlined for Example 649, 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (5.2 g, 21 mmol)) was reacted with ethyl bromide (2.6 g, 24 mmol) to afford the desired product (3.4 g, 59%) as colorless oil: ESI MS m/z 272 [C16H22BNO2+H]+.