Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[OH-].[Li+]>CS(C)=O.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:3]([CH:6]=1)[C:4]#[N:5])([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Temperature: 25 °C

Procedure:
Combine 2-amino-5-isopropyl-benzonitrile (3.19 g, 20 mmol), 1-fluoro-2-nitro benzene (2.1 mL, 20 mmol) and lithium hydroxide (1.68 g, 40 mmol) in DMSO (40.0 mL) and heat at 55° C. for 19 hours. Cool to ambient temperature and dilute with water (200 mL). The title compound precipitates as 4.56 g of an orange solid: mp 91–96° C.; mass spectrum (ion spray) m/z=280 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1)(=[O:25])=[O:24]
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: CC1(C)CC(=O)c2sc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3Cl)nc2C1

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (47.2 mg) with purity >90%: MS (pos) m/z 439.3, 441.3; HRMS m/z 437.9451 (calc. of monoisotopic mass for C15H13Cl3N2O3S2 gives 437.9433).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][O:8][C:9]1[C:10]([OH:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[OH-].[K+]>O1CCCC1.O>[CH3:1][N:2]([CH3:6])[C:3]([O:17][C:10]1[C:9]([O:8][CH3:7])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])=[S:4]
Reactant: CN(C)C(=S)Cl
Reactant: COc1cccc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C=O)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
A solution of N,N-dimethylthiocarbamoyl chloride (10 g) in tetrahydrofuran (40 ml) was added dropwise at <12° C. over 30 minutes to a stirred solution of 3-methoxy-2-hydroxybenzaldehyde (12.3 g) and potassium hydroxide (4.6 g) in water (105 ml) then the mixture was stirred at ambient temperature for 15 minutes. 10% Aqueous potassium hydroxide solution (30 ml) was added, then the product was extracted into toluene (3×150 ml). The combined extracts were washed with water (150 ml) then dried (MgSO4). The solvents were removed in vacuo and the residue was crystallised from methanol to give 2-(N,N-dimethylthiocarbamoyloxy)-3-methoxybenzaldehyde (10.5 g) as a yellow solid which was used without further purification.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12>CN1CCCC1=O.CN1C(=O)N(C)CC1.[Cl-].[Li+]>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CN1CCN(C)C1=O
Product: O=C1CCCCCCCCCCC1
Yield: 94 %

Procedure:
For example, German Patent DE3744094 discloses a technique where an epoxycyclododecane is isomerized by using N-methylpyrrolidone or N,N′-dimethylethyleneurea as a solvent and using lithium chloride as a catalyst and thereby a cyclododecanone is obtained in a yield of 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:36]O>>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxyphenylthio)-propyl]-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[S:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C([Mg]Br)(C)C.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:14][N:2]([CH3:1])[C:3](=[S:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(CC(=S)N(C)C)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C(C(=S)N(C)C)C2(O)CCCCC2)cc1
Yield: 62.9 %

Procedure:
N,N-Dimethyl-p-methoxyphenylthioacetamide (20.9 g) in toluene was added to a solution of 1.45M isopropyl magnesium bromide in methyl t-butyl ether (80 ml) and toluene (400 ml) under an inert atmosphere of nitrogen whilst the internal temperature was maintained below 10° C. After 2 hours a solution of cyclohexanone (9.82 g) in toluene (50 ml) was added to the reaction mixture under nitrogen. After a further 15 minutes the mixture was blown over onto 1N hydrochloric acid (150 ml). The organic phase was washed, dried and evaporated. Recrystallisation of the residue from di-isopropyl ether gave the title compound (19.3 g, 64% yield), melting point 132° to 3° C.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:27][CH:26]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-phenoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.95 (d, J=13 Hz, 2H), 2.11 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 4H), 4.38 (s, 1H), 7.00-7.09 (m, 4H), 7.17-7.23 (m, 1H), 7.38-7.44 (m, J=8, 8 Hz, 2H), 7.81-7.89 (m, 2H); MS (APCI/NH3) m/z 349 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH:22][C:23]([O:25]C(C)(C)C)=O)=[S:20])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:23](=[O:25])[NH:22][N:21]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(-c3ccc(C(=S)NNC(=O)OC(C)(C)C)cc3)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2)s1
Yield: 7 %

Procedure:
A mixture of tert-butyl 2-(4-(6-methoxyquinolin-2-yl)phenylcarbonothioyl)hydrazinecarboxylate (500 mg, 1.49 mmol) and AlCl3 (600 mg, 4.50 mmol) in anhydrous DCM (50 mL) was refluxed overnight. Reaction was cooled, followed by an aqueous/EtOAc workup. The residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound IV-33 (35 mg, yield 7%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.22 (brs, 1H), 10.22 (brs, 1H), 8.40-8.28 (m, 3H), 8.11 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.38 (dd, J=9.2, 2.8 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H). MS (ESI): m/z 321.7 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[O:24][N:23]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
A mixture of 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.19 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.054 g, 0.21 mmol), Cs2CO3 (0.067 g, 0.21 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4) and filtration was followed by concentration. The resulting material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.070 g, 76%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.88 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.44-1.35 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); MS m/z 493 (M+H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.CN(C)C(=O)C.Cl[S:43]([NH2:46])(=[O:45])=[O:44].Cl.C(=O)([O-])[O-].[Na+].[Na+].O>>[S:43](=[O:45])(=[O:44])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:46]
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (16) (11.5 g, 0.0221 mol) in N,N-dimethylacetamide (160 mL, 1.7 mol) was added chlorosulfonamide (6.64 g, 0.0575 mol), and the reaction stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C., at which point 12 M hydrochloric acid (90 mL, 1.1 mol) was added dropwise via an addition funnel over 25 min, keeping the internal reaction temp below 50° C. Once the addition was complete, the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was next quenched carefully via slow addition of a suspension of sodium carbonate (70.30 g, 0.6633 mol) in water (200.0 mL, 11.10 mol). The resulting suspension was filtered and the solids were rinsed with EtOAc (3 rinses, total—800 mL). The solids were set aside, and the filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted 3×EtOAc (total EtOAc—2000 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via column chromatography (applied with CH2Cl2, 400 g column, eluent 0-10% MeOH:CH2Cl2 over 80 min then 10% MeOH: CH2Cl2 for 20 min) to afford {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (10.3 g, 96%). LCMS: (FA) ES+ 485; 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.25 (s, 1H), 7.22-7.13 (m, 2H), 5.98 (s, 1H), 5.52 (d, J=32.8, 1H), 5.34 (s, 1H), 4.43-4.35 (m, 1H), 4.32 (dd, J=7.5, 9.8, 1H), 4.22 (td, J=2.5, 5.0, 1H), 4.16 (dd, J=7.3, 9.8, 1H), 3.34 (s, 4H), 3.10 (dd, J=2.1, 16.6, 1H), 3.02 (dd, J=4.8, 16.6, 1H), 2.58-2.46 (m, 1H), 2.28 (ddd, J=2.2, 6.9, 14.8, 1H), 2.12-1.90 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1>C(OCC)(=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]3[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:22][CH:23]=1
Reactant: Clc1nccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2nccnc2Cl)CC1
Temperature: 110 °C

Procedure:
To 2,3-dichloropyrazine (0.160 gm, 0.00107 mol) was added 4-fluorobenzyl 4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.86 gm, 0.00322 mol) and the resulting mixture heated under nitrogen at 110° C. for 30 min. The reaction was cooled, diluted with ethyl acetate (50 mL), and washed with 10% aqueous sodium/citric acid pH=5.2 (3×30 mL), and 10% aqueous sodium bicarbonate (30 mL). The ethyl acetate extract was dried over sodium sulfate, filtered through a pad of silica and concentrated to an oil. Crystallization from ether/hexane gave 4-[(3-chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid 4-fluoro-benzyl ester.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:41])[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([C:34]4[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=4)=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:41])[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([C:34]4[CH:39]=[CH:38][C:37]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:36][CH:35]=4)=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2)CC1
Yield: 37.9 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 32, the title compound (178 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH2:54]O>C1COCC1.C(OCC)(=O)C>[CH2:58]([O:57][C:53](=[O:56])[CH2:54][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]2[CH:32]=[CH:33][C:20]([CH2:19][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=3[CH3:18])=[CH:21][CH:22]=2)[CH:26]=1)[CH3:59]
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 61F (1.29 g, 2.93 mmoles), triphenylphophine (1.54 g, 5.86 mmoles), and di-t-butylazodicarboxylate (1.01 g, 4.40 mmoles) in anhydrous THF (6 mL) were treated with ethyl glycolate (0.35 mL, 3.66 mmoles). The reaction was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (hexanes to 10% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])(=[O:7])[CH3:6]>C(Cl)(Cl)Cl>[C:5]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C:14]1[C:15]([F:29])=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1C(c2ccc(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Solvent: ClC(Cl)Cl
Product: CC(=O)N1[C@@H](c2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Reaction time: 0.5 h

Procedure:
1 ml of fuming nitric acid was added to 59 mg of N-(4-((5S)-1-acetyl-5-methylpyrrolidin-2-yl)-3-fluorophenyl)pyrazine-2-carboxamide at room temperature, and the reaction liquid was stirred at the same temperature for 30 minutes. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduce pressure, and purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound as a pale yellow oily substance. (Rf: trans form>cis form.)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][C:21]=2[CH:28]=1.CO>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:28][C:21]=2[CH:22]=1)=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1cc2cc(Br)ccc2o1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 50 ml of toluene and 7.9 g of dibenzylamine are added dropwise with stirring at 50-60° C. in the course of 10 min. to 5.2 g of 5-bromobenzofuran-2-carbonyl chloride in 100 ml of toluene. A colourless solid is obtained. After dropwise addition is complete, the mixture is additionally stirred at 100-110° C. for a further 3 hours. After cooling to 10° C., the solid product (dibenzylammonium chloride) is filtered off with suction. The filtrate is then treated with a mixture of 150 ml of water and 10 g of sodium carbonate and thoroughly shaken. The organic phase is separated off, washed again with 100 ml of water, dried using sodium sulfate and filtered. The, filtrate is concentrated on a Rotavapor in vacuo to a residue (residue: 9.5 g). After recrystallization from 100 ml of methanol, 6.5 g of product (yield 77%) remain after isolation.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[CH:6]([O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[C:21](C(O)=O)[C:17]=3[NH:18][C:19]=2[CH:20]=1)=[O:11])([CH3:8])[CH3:7].C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>O>[C:4]([C:21]1[C:17]2[NH:18][C:19]3[CH:20]=[C:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[CH:13]=[CH:14][C:15]=3[C:16]=2[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1)(=[O:5])[NH2:2]
Reactant: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(-c3ccccc3)nc12
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Product: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12
Yield: 90 %

Procedure:
Dry DMF (10 mL) was added to a mixture of 7-(isopropoxycarbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylic acid (0.95 g, 2.54 mmol), NH4C1 (0.41 g, 7.6 mmol), EDC (1.46 g, 7.61 mmol), and 1-hydroxybenzotriazole hydrate (1.03 g, 7.61 mmol). After stirring for a few minutes, TEA (1.06 mL, 7.61 mmol) was added and the reaction left stirred overnight. It was diluted with water (200 ml) and the precipitate was collected by filtration, washed with water and dried to leave isopropyl 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylate (0.925 g, 2.28 mmol, 90% yield) as a yellow solid. MS (ESI) m/z 374.04 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.66 (1H, br. s.), 8.54 (1H, s), 8.46 (1H, s), 8.38 (1H, d, J=8.24 Hz), 8.33 (2H, d, J=7.32 Hz), 7.92-7.99 (1H, m), 7.88 (1H, dd, J=8.24, 1.22 Hz), 7.57 (2H, t, J=7.63 Hz), 7.46 (1H, t, J=7.32 Hz), 5.22 (1H, dt, J=12.51, 6.26 Hz), 1.39 (6H, d, J=6.41 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1ncccc1F
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ncccc2F)nc2nc(N)sc12
Yield: 38.8 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (348 mg, 1.16 mmol) and 2-((R)-1-chloroethyl)-3-fluoro-pyridine (240 mg, 1.5 mmol). Purification by flash column chromatography (eluent DCM: methanol gradient) resulted in 190 mg (47% yield) of the title compound with a diastereomeric excess of 60%.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1.Br[C:16]1[S:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:19]([CH3:21])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C:16]3[S:17][C:18]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCC1Cc1ccc(F)cc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(N2CCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33.1 %

Procedure:
A mixture of 3-(4-fluorobenzyl)pyrrolidin-2-one (0.074 g, 0.39 mmol), 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.32 mmol), cesium carbonate (0.16 g, 0.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (0.005 g, 0.006 mmol) and xantphos (0.007 g, 0.013 mmol) in anhydrous toluene (2 mL) was subjected to microwave irradiation at 80° C. for 35 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexanes (3/1)) to afford the title compound as a white solid (0.045 g, 33%): mp 169-170° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 1H), 7.14 (dd, J=8.0, 5.5 Hz, 2H), 6.95 (t, J=8.8 Hz, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.07-3.95 (m, 1H), 3.92-3.79 (m, 1H), 3.20 (dd, J=13.9, 4.5 Hz, 1H), 3.07-2.93 (m, 1H), 2.83-2.74 (m, 1H), 2.61 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.82 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.8, 163.4, 162.5, 155.5, 153.2, 149.3, 149.1, 135.7, 133.8, 133.7, 130.4, 123.7, 118.2, 115.6, 45.9, 44.4, 41.5, 35.6, 24.2, 17.3; MS (ES+) m/z 425.3 (M+1).