Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: Nc1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3ccccc3n2)ccc1-c1ccccn1

Procedure:
To a solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (130 mg, 0.42 mmol) in ethanol (5 mL) was added 2-aminopyridine (40 mg, 0.42 mmol). The resulting reaction mixture was heated to reflux for 2 h and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and washed with a solution of saturated aqueous NaHCO3 (3×10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:1 to 1:0) to afford 2-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[1,2-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.72 (d, 1H), 8.13 (d, 1H), 7.75 (s, 1H), 7.91 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.70 (dd, 1H), 7.66 (d, 1H), 7.57 (dd, 1H), 7.20 (m, 2H), 6.79 (dd, 1H), 4.00 (s, 3H) ppm. MS (ESI) 302 (M)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH2:25])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH:25][C:27](=[O:34])[C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5c(N)cccc45)[nH]c3c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5c(NC(=O)c6ccccc6)cccc45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
The 3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine of Example 743 is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:18]([CH:19]=[O:20])[C:9]2=[O:8])=[CH:24][CH:23]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc2ccccc2n(Cc2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Sodium hydride (60% in oil) (1.3 g) was added at 0° C. to a DMF solution (50 ml) of 2-oxo-1,2-dihydroquinoline-3-carboxaldehyde (5.13 g), followed by stirring for 30 minutes. 4-chlorobenzyl bromide (7.0 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, extraction with ethyl acetate was performed, and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:4). The purified product was recrystallized from a chloroform-diisopropyl ether mixed solvent to thereby obtain 6.57 g (yield: 72%) of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde as a white powder.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:11][C@@H:10]1[C@H:27]1[O:31]C(C)(C)[N:29]([C:34](=[O:36])[CH3:35])[C@H:28]1[CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:45][C:40]1[CH:39]=[C:38]([CH:43]=[C:42]([F:44])[CH:41]=1)[CH2:37][C@H:28]([NH:29][C:34](=[O:36])[CH3:35])[C@H:27]([OH:31])[C@H:10]1[CH2:11][C@@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:13][NH:9]1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3cccc(OC(F)(F)F)c3)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCc2cccc(OC(F)(F)F)c2)CN1
Reaction time: 18 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (5 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-trifluoromethoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.138 g, 0.22 mmol). Stir 18 h and concentrate to give the title compound as a foam (0.11 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][CH:21]([CH2:23][O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:20][C:19]=4[CH:32]=3)=[O:14])[C:6]=2[O:5][C:4]([C:33]#[N:34])=[CH:3]1.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][CH:21]([CH2:23][O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:20][C:19]=4[CH:32]=3)=[O:14])[C:6]=2[O:5][C:4]([C:33]2[NH:37][N:36]=[N:35][N:34]=2)=[CH:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12)c1ccc2c(c1)CC(COCc1ccccc1)O2
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 33.9 %

Procedure:
A mixture of N-[4-oxo-2-cyano-4H-1-benzopyran-8-yl]-2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamide (300 mg, 0.66 mmol), sodium azide (129 mg, 1.99 mmol), ammonium chloride (107 mg, 1.99 mmol) and dry N,N-dimethylformamide (10 ml) was left under stirring at 100° C. for 1.25 h. After that the mixture, cooled at room temperature, was poured onto a 1M hydrochloric acid solution (10 ml), recovering by filtration the formed precipitate, thereby obtaining 111 mg of the title compound as a white solid with melting point 200-202° C., which was purified by crystallization in methanol:dichloromethane mixtures (68% yield).
Reaction SMILES: [OH-].[K+].[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([O:28]C)=[O:27])=[CH:23][C:22]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[C:21]([O:35][CH3:36])[CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[K]>CO.O>[N:3]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[C:17]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:46])[F:45])[CH:38]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=[O:27])=[CH:23][C:22]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[C:21]([O:35][CH3:36])[CH:20]=4)[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Potassium hydroxide (1.86 g, 33.1 mmol) was added to a solution of methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.1 g, 3.31 mmol) in methanol (60 mL) and water (20 mL). The mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with water. The methanol was removed in vacuo. The solid precipitate was collected by filtration, washed with cold water, and air dried to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 92% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.11 (s, 1H), 7.91 (d, J=7.78 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.67 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 4.04 (s, 3H), 3.42-3.52 (m, 4H), 2.33 (br. s., 4H), 2.03 (t, J=11.80 Hz, 1H), 1.82 (t, J=11.29 Hz, 2H), 1.39-1.48 (m, 6H), 1.30-1.39 (m, 2H), 1.12 (t, J=7.40 Hz, 3H), 0.97-1.09 (m, 2H); MS (m/z) 620.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]=1[NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O-:15])=[O:14]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
A mixture of 3-amino-1-propanol (6.77 mL, 89.0 mmol), 2-chloro-1,3-dinitrobenzene (15.0 g, 74.1 mmol), triethylamine (12.4 mL, 89.0 mmol) and tetrahydrofuran (370 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (17.7 g, 73.3 mmol, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@H:7]([NH:10][S@](C(C)(C)C)=O)[CH2:8][CH3:9].[ClH:17].O>CO.O1CCOCC1>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@H:7]([NH2:10])[CH2:8][CH3:9]
Reactant: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-pyrimidin-2-yl-propyl)-amide (Comp. No. 14b) (2.6 g, 10.8 mmol) in methanol was added 4 M hydrogen chloride in dioxane (4.35 ml) and the mixture was stirred for 1 h at 25° C. Water (100 ml) was added and the aqueous phase was washed with methyl tert-butyl ether. The aqueous layer was freeze-dried to give 1.7 g (75%) of (R)-1-pyrimidin-2-yl-propylamine hydrochloride. LC/MS (method 5): Rt=0.68 min; m/z=138.15 (M+H+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12](I)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:18])(=[O:4])=[O:3].[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:27]2[N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:18])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1cc(I)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 92.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-methanesulfonyloxy-5-methoxy-7-iodoisoindolinone (50.0 mg, 0.130 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with 1-(tert-butoxycarbonyl)indole-2-boronic acid (68.1 mg, 0.261 mmol), palladium acetate (2.3 mg, 0.010 mmol), tri(o-tolyl)phosphine (6.3 mg, 0.021 mmol) and triethylamine (0.181 mL, 1.30 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=7/3 to 1/1 to 3/7) to obtain 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (56.9 mg, yield 93%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][C:27]([C:48]#[N:49])=[N:28][C:29]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:12][C@@H:11]1[C:50]([NH:52][CH2:53][CH3:54])=[O:51])(=O)C1C=CC=CC=1.N>C(O)C>[C:48]([C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[C@@H:13]2[O:12][C@H:11]([C:50]([NH:52][CH2:53][CH3:54])=[O:51])[C@@H:10]([OH:9])[C@H:14]2[OH:15])=[C:29]([NH:33][CH2:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:28]=1)#[N:49]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A solution of (2S,3S,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 7) (4.75 g, 6.59 mmol) in ethanol (200 ml) was saturated with ammonia gas and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to afford the title compound as a solid (2.80 g).
Reaction SMILES: [I:1]I.[Si:3]([N:10]1[C@@H:13]([CH2:14]O)[CH2:12][C:11]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1>CC#N>[Si:3]([N:10]1[C@@H:13]([CH2:14][I:1])[CH2:12][C:11]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CI
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.2 %

Procedure:
Iodine (4.25 g, 16.7 mmol) was added to a solution of 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (2.25 g, 10.47 mmol), Ph3P (5.48 g, 20.93 mmol) and imidazole (1.64 g, 24.07 mmol) in MeCN (100 mL) at 0°. After stirring at room temperature for four days, the mixture was concentrated and suspended in EtOAc-hexane (1:1). The suspension was filtered through a silica gel pad and washed with EtOAc-hexane (1:1). Concentration of the filtrate and purification by flash chromatography (SiO2, 10% EtOAc-hexane) afforded pure 1-(tert-butyldimethylsilyl)-4(R)-(iodomethyl)azetidin-2-one as a white solid (2.73 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 3.72-3.66 (m, 1H), 3.50 (ddd, J=9.8, 3.2, 0.6 Hz, 1H), 3.21 (ddd, J=15.6, 5.4, 0.6 Hz, 1H), 3.11 (dd, J=9.8, 9.8 Hz, 1H), 2.76 (dd, J=15.6, 2.5 Hz, 1H), 0.96 (s, 9H), 0.27 (s, 3H), 0.22 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccccc3)C2=O)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and benzyl bromide, to give the desired product as a light yellow solid (58%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH2:12][CH2:13][CH3:14])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=2[S:19](=[O:33])(=[O:32])[N:18]=1.[OH-].[Na+:35]>O>[CH3:15][C:5]1([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:4]1=[O:16].[Na+:35]
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A suspension of the product of Example 32C (0.049 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.099 mL, 0.098 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.043 g, 86%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.64 (m, 4 H) 0.89 (m, 1 H) 1.38 (m, 3 H) 1.68 (m, 1 H) 2.10 (m, 1 H) 2.93 (m, 3 H) 7.28 (m, 3 H) 7.45 (m, 3 H) 8.05 (m, 1 H) 9.85 (m, 1 H) 15.42 (m, 1 H). MS (ESI−) m/z 488 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Cl.[C:9]([Cl:12])(C)=O.CCOCC>CO>[NH2:1][C@@H:2]([C:5]([O:7][CH3:9])=[O:6])[CH2:3][SH:4].[ClH:12]
Reactant: N[C@H](CS)C(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](N)CS
Yield: 80.7 %

Procedure:
To a cooled (0° C.) solution of H-D-Cys-OH.HCl (2.0 g, 0.013 mol) in 89.0 mL of MeOH was added 4.5 mL (0.063 mol) of AcCl. The resulting colorless solution was heated at reflux for 5 h, cooled, concentrated on a rotary evaporator, and then stripped down with Et2O until a white solid resulted. Additional Et2O (~100 mL) was added, the solid filtered, washed with Et2O, and excess solvent removed in vacuo to provide H-D-Cys-OMe.HCl as a white solid (1.80 g). The synthesized compound was identical (1H NMR) to commercially available H-Cys-OMe.HCl (Sigma).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(C)C=CC=C[CH:12]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:11]([O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(Br)c1

Procedure:
To a suspension of 2-bromo4-pyridine carboxylic acid (prepared according to the method of Ashimori, Chem. Pharm. Bull. 38 (9) 2446-2458 (1990)) in 2:1 toluene: absolute ethanol (45 mL) was added sulfuric acid (0.75 mL). The mixture was heated at reflux for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with chloroform (3 times). The combined chloroform extracts were dried over magnesium sulfate, filtered and concentrated afforded the crude product as a yellow oil. Purification by silica gel chromatography eluting with 9:1 hexane:ethyl acetate to afford the title compound (900 mg) as a clear, colorless oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([CH3:16])[CH:12]([OH:15])[C:13]#[CH:14].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:15][CH:12]([C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1)[CH:11]([CH3:16])[CH3:10]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CC(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(O)C(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Ethyl chlorooximidoacetate (6.79 mmol, 1.029 g) and 4-methyl-1-pentyn-3-ol (20.38 mmol, 2 g) were dissolved in toluene (20 ml). Et3N (6.79 mmol, 0.947 ml) dissolved in toluene was added dropwise. The mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.828 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 0.92 (d, 3H), 0.97 (d, 3H), 1.39 (t, 3H), 2.03-2.16 (m, 1H), 4.41 (q, 2H), 4.58 (d, 1H), 6.65 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:23])[NH:10][CH:11]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:23])[NH:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([CH3:1])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Yield: 97.2 %

Procedure:
A solution of 6.9 g (20 mmol) of [1-methyl-2-oxo-2-[(1-(phenylmethyl)-3-pyrrolidinyl)amino]ethyl]-carbamic acid 1,1-dimethylethyl ester in 100 ml of methanol was treated with 1.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at pressures of 33.6 to 52.7 psi and temperatures of 23.5°-27.0 for 18 hours. The catalyst was removed by filtration and the solvent evaporated to give 5.0 g of the title compound as a viscous liquid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16][NH2:17])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:18])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cn1
Reaction time: 24 h

Procedure:
A solution of 6-chloronicotinonitrile (1.00 g, 7.2 mmol), glycine tert-butyl ester (1.04 g, 7.9 mmol) and DIEA (4.9 mL, 29 mmol) in anhydrous dioxane (20 mL) was heated at reflux. After 24 hours, an additional amount of glycine tert-butyl ester (0.5 g, 3.8 mmol) was added. After 24 additional hours at reflux, the reaction mixture was concentrated under reduced pressure. The residue was taken up with EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. After precipitation from EtOAc/Et2O/heptane, the title compound was obtained as an off-white powder (1.55 g, 92%). HPLC (Method A), Rt: 3.1 min (purity: 95.1%). UPLC/MS, M+(ESI): 178.0 ([M-tBu+2H]+), M−(ESI): 232.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (d, J=2.1 Hz, 1H), 7.91 (m, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.98 (d, J=6.1 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNCC1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure B.