Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[S:33](Cl)(=[O:36])(=[O:35])[NH2:34]>CN(C)C(=O)C>[S:33](=[O:36])(=[O:35])([O:28][C@:25]1([C:29]([F:32])([F:31])[F:30])[CH2:24][C@@H:4]2[CH2:5][CH2:6][CH2:7][C:8]3[C:9](=[CH:10][C:11]4[CH:12]=[N:13][N:14]([C:17]5[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=5)[C:15]=4[CH:16]=3)[C@@:3]2([CH2:1][CH3:2])[CH2:27][CH2:26]1)[NH2:34]
Reactant: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC[C@]12CC[C@@](OS(N)(=O)=O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 74 %

Procedure:
(3S,4aS,12bS)-12b-Ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.125 g, 0.280 mmol) in N,N-dimethylacetamide (3 mL) was stirred and treated with sulfamoyl chloride (0.105 g, 0.91 mmol). After about 3 h sulfamoyl chloride (0.080 g, 0.69 mmol) was added and the mixture was stirred for about 14 h at rt. The reaction mixture was purified without manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 um particle size) with a gradient of 25-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then diluted with water (15 mL). The solids were collected by filtration then washed with water (5 mL) and dried to yield (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-yl sulfamate (109 mg, 74%); LC/MS, method 2, Rt=2.86 min, MS m/z 526 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.8 Hz, 1H), 8.02 (s, 2H), 7.86 (s, 1H), 7.81-7.78 (m, 2H), 7.57 (s, 1H), 7.45-7.37 (m, 2H), 3.23-3.18 (m, 2H), 2.98-2.92 (m, 1H), 2.45-2.18 (m, 4H), 2.16-1.95 (m, 3H), 1.94-1.61 (m, 4H), 1.42-1.27 (m, 1H), 0.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC(=O)C3)nc1
Yield: 49 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-2-tetralone (Journal of Organic Chemistry (1999), 64(26), 9719-9721) (1.55 g, 9.55 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K2CO3 (1.98 g, 14.3 mmol) gives the title compound (1.32 g), after purification on silica gel (50% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.59 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.47 (s, 1H), 7.19 (d, 2H), 7.07 (m, 2H), 6.97 (d, 1H), 3.59 (s, 2H), 3.01 (t, 2H), 2.43 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15]([C:16]2[CH:17]=[C:18]([S:26][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[O:27])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: O=C(O)CCCCBr
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCCCC(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.115 g, 264 μmol, Example 216, intermediate a) in acetonitrile (2 mL) were added 5-bromopentanoic acid (59.6 mg, 329 μmol) and DIPEA (85.1 mg, 115 μL, 659 μmol). After the addition of DIPEA the white suspension turned to a light yellow solution, which was stirred at room temperature for 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 0:0). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.10 g; 70%). MS (ESI): m/z=537.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[H-].[Na+].[C:33](Cl)(=[O:35])[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:33](=[O:35])[CH3:34])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(CNc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(4-methoxybenzylamino)imidazo[1,2-b]pyridazine-3-carboxamide 19A (80 mg, 0.187 mmol) in DMF (2 mL) was added 60% NaH (18.74 mg, 0.469 mmol). The mixture was stirred for 20 minutes and then a solution of acetyl chloride (0.038 mL, 0.540 mmol) in DMF (0.4 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was quenched with sat. NH4Cl. The light brown solid was collected by filtration, washed with water and dried under vacuum to give 19B (78 mg, 89%). {M+H]=469. HPLC Peak Rt=2.303 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCC1.[CH3:12][O:13]C=O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13].[C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:18])[CH3:17]
Reactant: C1CCNCC1
Reactant: COC=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCNC1
Product: CC(=O)N1CCCCC1
Product: O=CN1CCCCC1

Procedure:
As starting compound in the process of the invention there is used as 1-acyl-2-alkoxypiperidine or pyrrolidine of the formula II, which is preferably obtained by electrochemical alkoxylation of 1-acyl-piperidine or pyrrolidine. The latter compounds can be obtained, for example, by reacting piperidine or pyrrolidine with an acylating agent, for example an acid chloride, an acid anhydride or an ester; there are mentioned, for example, the reactions of piperidine with a formic acid methyl ester (K. Auwers, Z.f. physik. Chemie, 15, 45 (1894) or acetic anhydride (A. W. Hofmann, Ber.Deut.Chem.Ges., 16, 588 (1883), in which 1-formylpiperidine or 1-acetylpiperidine is obtained in a yield of about 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13]([O:27]C)=[N:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a well stirred solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (10 g) in THF (200 mL) at room temperature was added aqueous 6 N hydrochloric acid (10 mL). The stirring was continued for 3 h. Solvent was evaporated and the residue was dried under vacuum to obtain the product as a white powder (9.7 g, 100%); m.p. 185-186° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([C:16](=O)[CH3:17])[C:14]#[N:15].O.[NH2:20][NH2:21]>C(O)C>[CH3:17][C:16]1[C:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])=[C:14]([NH2:15])[NH:21][N:20]=1
Reactant: NN
Reactant: CC(=O)C(C#N)Cc1cccc(C(F)(F)F)c1C
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (3.5 g, 33.2 mmol) in N,N-Dimethylformamide (25 mL) stirred under nitrogen at 0° C. was added a solution of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.0 g, 27.7 mmol) in 10 ml of DMF dropwise during 30 min. The reaction mixture was stirred at 40° C. for 2 hours. Then this solution was diluted with saturated ammonium chloride solution. This solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried, concentrated to dryness in vacuo. The crude product was purified with on a silica gel column to give 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3-oxobutanenitrile. (5.2 g, 74%). To a solution of 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}3-oxobutanenitrile (5.2 g, 20.4 mmol) in ethanol (400 mL) stirred under nitrogen at 20° C. was added neat hydrazine monohydrate (2.25 g, 30.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 100° C. for overnight. After cooled to room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified on a silica gel column (methanol/DCM gradient solvent system) to provide titled product. (2.16 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (s, 3H) 2.39 (s, 3H) 3.63 (s, 2H) 4.30 (br. s., 2H) 7.19 (d, J=7.58 Hz, 1H) 7.27 (t, J=7.71 Hz, 1H) 7.49 (s, 1H) 11.09 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].C(O[O:15][C:16]([CH3:19])(C)C)(C)(C)C.[C]=O.[CH2:22]([OH:24])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:22]([O:15][CH2:16][CH3:19])=[O:24]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Reactant: Cc1c(Cl)cccc1Cl
Agent: [C]=O
Product: CCOC(=O)Cc1c(Cl)cccc1Cl
Temperature: 120 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
2,6-Dichlorotoluene (2.4 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 84 mg ethyl 2,6-dichlorophenylacetate was obtained by column chromatography, in a yield of 72%. 1HNMR (400 MHz, CDCl3) δ 1.25 (t, J=7.2 Hz, 3H), 4.01 (s, 2H), 4.17 (q, J=7.2 Hz, 2H), 7.14-7.18 (m, 1H), 7.31-7.33 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 36.8, 61.1, 128.0, 128.9, 131.4, 136.1, 169.5; HRMS (ESI) calcd. for C10H10Cl2NaO2 [M+Na]: 254.9950. found: 254.9949. The ethyl 2,6-dichlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 71 mg product 2,6-dichlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 95%.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:77]([O:80][CH3:81])[O:78][CH3:79])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=2[N:66]([CH3:76])[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:79][O:78][CH:77]([O:80][CH3:81])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=3[N:66]([CH3:76])[S:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=2)(=[O:69])=[O:68])=[N:46][CH2:45]1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CSc1ccccc1
Product: COC(OC)C1CN=C(c2cc3cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
A mixture of triphenylphosphine oxide (1.17 g), trifluoromethanesulfonic anhydride (1.18 g) and dichloromethane (30 mL) was stirred for 15 min under ice-cooling. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (2.65 g) and thioanisole (940 mg) in dichloromethane (10 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 30 min under ice-cooling. The reaction mixture was diluted with ethyl acetate, and extracted with 3N hydrochloric acid. The aqueous layer was alkalified with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:8-1:9, volume ratio) to give the title compound (840 mg, yield 38%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.INC(=O)CCC(N)=O.[NH2:25][C:26]([NH2:28])=[S:27]>C(OCC)(=O)C.CO>[NH2:28][C:26]1[S:27][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)[N:25]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1cnc(Cl)cn1
Agent: NC(=O)CCC(=O)NI
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N)nc1-c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
Ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate (Intermediate 45, 2.0 g, 8.77 mM) was dissolved in ethyl acetate (30 mL), to this amberlyst resin (2.0 g) and N-iodosuccinamide (2.1 g, 9.64 mM) were added and stirred for 1 h at room temperature. The resin was filtered and the filtrate was concentrated under reduced pressure to afford crude compound, which was dissolved in methanol (25 mL). Thiourea (0.99 g, 13.15 mM) was added to the reaction mixture and the reaction mixture was heated to reflux for 2 h. The methanol was concentrated under reduced pressure and the resulting residue was partitioned between sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure to obtain crude compound which was purified by flash column chromatography (gradient up to 50% of ethyl acetate/pet ether) to afford 500 mg (20.06%) of ethyl 2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CC#N>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in MeCN (1.5 mL) was added triethylamine (64 uL, 0.47 mmol) and methane sulfonyl chloride (36 uL, 0.47 mmol). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the product isolated by Prep HPLC (low pH) as an off white/pink solid (36 mg, 0.078 mmol, 49% yield).
Reaction SMILES: [CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH:9][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH2:4][CH2:3]1
Reactant: CCCC(=O)Cl
Reactant: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC1(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution of 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain N-[2-(1-methylcyclopropyl-ethynyl)-4-nitro-phenyl]-butyramide (230 mg, 82%), which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:38]2[CH2:39][CH2:40][N:35]([C:28]3[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=3)[CH2:36][CH2:37]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc([N+](=O)[O-])c1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Yield: 54.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dinitrophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10]>CO.[Pd]>[NH2:27][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][CH3:26])[O:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:4]2[CH2:5][CH2:6][CH2:7][CH:3]2[CH2:2][OH:1])[CH:17]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1N

Procedure:
2-(2-Hydroxymethyl-pyrrolidin-1-yl)-N-[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]-acetamide was hydrogenated in methanol in the presence of Pd/C for 4 hours. The catalyst was removed via filtration through Celite and filtrate was concentrated to give N-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamide. MS: MH+=372.4.
Reaction SMILES: Cl.[CH2:2]([NH:9][C@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[CH2:2]([N:9]([C@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])[C:20](=[O:21])[CH2:19][Cl:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](CO)N(Cc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of (R)-2-(benzylamino)-3-hydroxypropanoic acid hydrochloride (9.4 g, 48.2 mmol) and sodium hydroxide (2.57 g, 82.9 mmol) in H2O (30 mL) at 0° C. was added drop wise chloroacetyl chloride (4.9 mL, 62.1 mL) while maintaining the temperature below 10° C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted with CH2Cl2 (2×250 mL) and the organic layer dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10 to 30% CH3OH in CH2Cl2 with 1% acetic acid) to provide (R)-2-(N-benzyl-2-chloroacetamido)-3-hydroxypropanoic acid (2.6 g, 20%) as a yellow foam. 1H NMR consistent.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1.S(C)C.[OH-:21].[Na+].OO>C1COCC1>[OH:21][CH2:16][CH2:15][CH2:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13])[C:3]([OH:2])=[O:17]
Reactant: [OH-]
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(CCCO)c1OC
Temperature: 23 °C
Reaction time: 1.2 h
Yield: 89 %

Procedure:
To a solution of 3-allyl-4,5-dimethoxybenzoic acid methyl ester (Example 30, Step 1, 10.2 g, 43.2 mmol) in THF (100 mL) at 0° C. was added BH3.SMe2 (4.10 mL, 43.2 mmol). After 45 min the reaction mixture was warmed to 23° C. After stirring for 1.2 h the reaction was cooled to 0° C. and slowly treated with 3.0 N NaOH (39 mL) followed 10 min later by addition of H2O2 (30 weight %, 60 mL). Following the addition, the mixture was allowed to reach 23° C., then heated to reflux for 2 h. After cooling to room temperature, the mixture was partitioned between brine (400 mL) and EtOAc (500 mL). The aqueous layer was separated and extracted with EtOAc (400 mL). The organic layer was discarded and the aqueous was adjusted to pH 5 by addition of 1.0 N HCl then the product was extracted with EtOAc (2×500 mL). The organic layer was dried over MgSO4 and then concentrated in vacuo to give 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (9.24 g, 89%) of the desired alcohol, which was used without further purification. ESMS: m/z 239.3 [M−H].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][NH2:20].[NH4+:21].[OH-].O>>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][NH:20][C:2]1[N:11]=[C:10]([NH:21][CH2:19][CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: [NH4+]
Reactant: NCCc1cccs1
Agent: [OH-]
Solvent: O
Product: c1csc(CCNc2nc(NCCc3cccs3)c3ccccc3n2)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
A mixture of 1.4 g of 2,4-dichloroquinazoline and 3.5 g of 2-(2-thienyl)ethylamine was stirred under nitrogen at 160°-165° C. for one hour, then cooled. To the mixture 200 ml of a 50/50 mixture of NH4OH/water was added. The product was extracted into CH2Cl2, and this solution was concentrated to dryness. The residue was purified by HPLC (silica gel, 80% pentane/20% EtOAc) to provide 1.3 g of the title product Yield: 50.0% M.P. oil.