Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:3])[CH3:2].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]([CH:22]=O)=[CH:18][CH:19]=[CH:20][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH2:15][CH2:14]1
Reactant: CC(C)c1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: CC(C)c1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
100 mg of the target compound (0.27 mmol, 49.1%) was obtained using 1-(2-isopropylphenyl)piperazine (223 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:46][CH:47]([CH3:52])[C:48]([CH3:51])([OH:50])[CH3:49]>CN1CCCC1=O.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12]([NH:46][CH:47]([CH3:52])[C:48]([OH:50])([CH3:51])[CH3:49])[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CC(N)C(C)(C)O
Reactant: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(S(C)(=O)=O)nc2n1-c1c(F)cccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(NC(C)C(C)(C)O)nc2n1-c1c(F)cccc1F
Temperature: 120 °C

Procedure:
To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 14, (0.30 g, 0.59 mmol)) in N-methylpyrrolidinone (4 mL) is added diisopropylethylamine (0.41 mL, 2.36 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.10 g, 0.71 mmol). After heating the reaction at 90° C. for 21 hours, an additional equivalent of 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.08 g, 0.59 mmol) is added and the mixture heated at 120° C. for 4 hours. The reaction is cooled to room temp and then diluted with aqueous saturated NH4Cl solution. The aqueous phase is twice extracted with CHCl3 and the organic phase is then washed with aqueous saturated NaHCO3 solution. The organic phase is dried (MgSO4), filtered, concentrated in vacuo and the resulting residue is purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, d3-DMSO) δ 8.64 (s, 1H), 7.64-7.52 (m, 1H), 7.38-7.24 (m, 5H), 7.14-7.08 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 4.31 (bd s, NH), 3.85 (q, J=7.2 Hz, 2H), 3.34 (m, 1H), 1.04 (s, 9H), 0.93 (t, J=7.2 Hz); ESI+ MS: m/z (rel intensity) 541.0 (100, M++H).
Reaction SMILES: O[N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1csc2c1N(O)CCC2
Product: CCOC(=O)c1csc2c1N(Cl)CCC2

Procedure:
A solution of 2.25 g of ethyl 4-hydroxy-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate (see example 20) in 10 ml of phosphorous oxychloride is refluxed for 1 hour. After cooling excess reagent is distilled off under reduced pressure, the residue dissolved in 40 ml of dichloromethane and washed with 20 ml of 2N NaOH solution and 20 ml of water. After drying over magnesium sulfate, the filtrate is slurried with 500 mg of charcoal, filtered and evaporated to dryness. The residue is recrystallized from ether/pentane to yield ethyl 4-chloro-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate, mp 69°-70°.
Reaction SMILES: N1CCCCC1.[Br:7][C:8]1[CH:9]=[C:10]([C:13]#[CH:14])[S:11][CH:12]=1.I[C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1>C1COCC1.[Cu]I>[Br:7][C:8]1[CH:9]=[C:10]([C:13]#[C:14][C:16]2[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[S:11][CH:12]=1
Reactant: C#Cc1cc(Br)cs1
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Brc1csc(C#Cc2ccc(OCCN3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 0.3 mL (3.13 mmol) piperidine, 14.9 mg (0.08 mmol) CuI and 90.3 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 293 mg (1.56 mmol) 4-bromo-2-ethynyl-thiophene and 620 mg (1.56 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reaction mixture is stirred overnight at RT. To complete the reaction another 150 mg (0.8 mmol) 4-bromo-2-ethynyl-thiophene are added and the mixture is stirred for a further 24 h at RT. The mixture is evaporated down i. vac., the residue is triturated with EtOAc and the insoluble ingredients are filtered off. After the solvent has been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][CH2:18][N:19]([CH2:29][CH2:30][Cl:31])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.C1C2C(=NC3C(C=2NC2C=C(C=C(CO)C=2)N)=CC=CC=3)C=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:16][CH2:17][CH2:18][N:19]([CH2:29][CH2:30][Cl:31])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Reactant: CN(C)CCC(=O)Nc1cccc(N)c1
Agent: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(3-aminophenyl)-3-(dimethylamino)propanamide (1.15 g, 5.5 mmol) in dry DMF (20 mL) containing TEA (1.6 mL) was added a solution of N,N-bis(2-chloroethyl)-4-isocyanatoaniline [7, freshly prepared from N1,N1-bis-(2-chloroethyl)benzene-1,4-diamine hydrochloride 6 (3.4 g, 11 mmol) and triphosgene in chloroform] in dry DMF (5 mL)) at room temperature. After being stirred overnight at room temperature, the solid was filtered and washed with dry DMF. The filtrate was evaporated to dryness in vacuo and the product was purified by column chromatography using CHCl3/MeOH (100:10 v/v) as an eluent. The fractions containing main product were combined and evaporated to dryness under vacuum to afford compound N-(3-(3-(4-(bis(2-chloroethyl)amino)-phenyl)ureido)phenyl)-3-(dimethylamino)-propanamide (BO-2091), 2.2 g (62%); mp 88-90° C. The HCl salt of BO-2091 was prepared by treating the compound with HCl/EtOAc in a mixture of EtOAc:MeOH (10:1, v/v, 50 mL) under argon atmosphere during 30-40 min at room temperature. Solvent was then evaporated to dryness to give HCl salt of BO-2091. 1H NMR (DMSO-d6) δ: 2.77 (6H, s, CH3), 2.84-2.87 (2H, t, J=7.1 Hz, CH2), 3.32-3.35 (2H, t, J=6.7 Hz, CH2), 3.68-3.70 (8H, m, CH2), 6.71-6.73 (2H, d, J=8.6 Hz, Ar—H), 7.27-7.29 (2H, d, J=8.8 Hz, Ar—H), 7.36-7.38 (2H, d, J=8.8 Hz, Ar—H), 7.48-7.50 (2H, d, J=8.8 Hz, Ar—H), 7.95 (1H, brs, NH), 8.82 (1H, brs, NH), 9.02 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 30.50, 41.00, 42.10, 52.52, 52.58, 112.95, 117.95, 119.74, 120.02, 130.64, 132.64, 135.77, 140.96, 152.85, 167.25. HRMS [ES+]: calcd for C22H29Cl2N5O2, 466.4040 [M+H]+. found 466.1771. HPLC 98.7%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][N:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)[CH2:37][CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCOCC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (360 mg, 0.92 mmol), 1-(tetrahydropyran-4-yl)piperazine (250 mg, 1.47 mmol) and molecular sieves (4 Å, powdered, 1.5 g) in DCE (10 mL) was stirred at ambient temperature for 6 h. Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc: MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 495 as a cream foam (439 mg, 87%). LCMS (Method I): RT=2.50 min, M+H+=546. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.76 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 4.03 (d, J=11.3 Hz, 2 H); 3.87 (m, 7 H); 3.78 (s, 2 H); 3.42-3.29 (m, 4 H); 2.64 (m, 8 H); 1.79 (m, 3 H); 1.62 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])=[CH:12][CH:11]=1)([O-:9])=[O:8]>>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH2:17][CH2:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])=[O:2])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CCOC(C)(C)CCCC(C)CCSc1ccc([N+](=O)[O-])cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)CCS(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To 210 ml. of a 0.5M solution of sodium metaperiodate (aqueous methanol 1:1) at 0° is added 0.1 mol of 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfide. The mixture is stirred at 0° for 4 hours and then filtered to remove precipitated sodium iodate. The filtrate is diluted with water and then extracted with chloroform. The extract is dried over magnesium sulfate and solvent removed by evaporation to yield 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfoxide.
Reaction SMILES: [CH3:1][C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42]Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC#N.CCN(C(C)C)C(C)C>[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(C)(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccn2)nc2ccccc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(1-methyl-1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione in dry CH3CN, N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole, DIPEA and KI gave 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3) δ 1.18-1.33 (m, 2H), 1.39-1.54 (m, 2H), 1.52 (s, 6H), 1.71 (s, 9H), 2.65 (t, 2H, J=7.5 Hz), 3.43 (t, 2H, J=7.2 Hz), 4.27 (s, 2H), 7.04 (t, 1H, J=4.8 Hz), 7.19-7.31 (m, 3H), 7.55 (td, 1H, J=7.7, 1.7 Hz), 7.62-7.70 (m, 2H), 7.70-7.78 (m, 2H), 7.81 (dd, 1H, J=6.6, 1.6 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=3.9 Hz). Deprotection with H2NNH2.H2O using General Procedure E gave a colorless oil. Conversion to the HBr salt gave COMPOUND 222 as a white solid. 1H NMR (D2O) δ 1.36-1.51 (m, 4H), 1.60 (s, 6H), 2.46-2.59 (m, 2H), 2.72-2.84 (m, 2H), 4.56 (s, 2H), 7.54-7.64 (m, 2H), 7.74-7.84 (m, 2H), 8.03 (t, 1H, J=6.6 Hz), 8.21 (d, 1H, J=8.4 Hz), 8.64 (t, 1H, J=7.8 Hz), 8.85 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 23.21, 24.88, 26.01, 39.43, 45.77, 53.70, 63.80, 114.23, 125.75, 126.73, 126.84, 131.03, 142.12, 148.73, 153.74, 160.26; ES-MS m/z 338 (M+H). Anal. Calcd. for C20H27N5.3.0HBr.1.4H2O.0.3C4H10O: C, 40.57; H, 5.75; N, 11.16; Br, 38.19. Found: C, 40.48; H, 5.67; N, 11.01; Br, 38.18.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:14]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Yield: 78 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 2.99 mmol) reacted with N,N-diethylethylenediamine (4.62 mL) to give 6.19 g (78%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.O.OO>CO>[CH3:7][N:6]1[C:2]([S:1][S:1][C:2]2[N:6]([CH3:7])[N:5]=[N:4][N:3]=2)=[N:3][N:4]=[N:5]1
Reactant: Cn1nnnc1S
Agent: OO
Solvent: CO
Solvent: O
Product: Cn1nnnc1SSc1nnnn1C

Procedure:
Within a flask having a capacity of 1000 ml, 5-mercapto-1-methyltetrazole of 1000 mmol is solved in methanol of 450 ml, and the solution thus formed is cooled by water bathing. Into the solution thus prepared, 34.5% hydrogen peroxide of 20 ml is dropped slowly. At several minutes after dropping, the reaction generates heat, thus creating precipitate.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:7]=2.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH3:34][N:15]([C@H:11]1[CH2:10][C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[C:6]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH2:13][CH2:12]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CI
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C[C@H](NC(=O)OC(C)(C)C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCc2c(c3cc(S(=O)(=O)c4ccccc4)ccc3n2C)C1
Temperature: 25 °C
Reaction time: 1.1 h
Yield: 75.7 %

Procedure:
A solution of tert-butyl (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamate (1.74 g, 3.95 mmol) in DMF (13.0 mL) was added to a 0° C. suspension of 60% sodium hydride (0.38 g, 9.62 mmol) in DMF (3.0 mL) and stirred at room temperature for 1.1 hours. Methyl iodide (0.30 mL, 4.81 mmol) was added, and the reaction was stirred at room temperature for 2.0 hours. The reaction was cooled to 0° C., quenched with water and filtered. The filtrate was concentrated in vacuo, combined with the previously filtered solid and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to dryness, the residue was recrystallized from EtOAc/hexane to give 1.36 g (76%) of tert-butyl methyl[(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate as a colorless solid: mp 181.4-183.2° C.; [α]D=+103° (c 1.02, DMSO); 1H NMR (400 MHz, DMSO-d6) δ 8.06, 7.93-7.91, 7.62-7.53, 4.22, 3.64, 2.96-2.92, 2.84-2.79, 1.99-1.94, 1.42; 13C NMR (100 MHz, DMSO-d6) δ 155.6, 142.8, 138.7, 138.0, 132.7, 130.5, 129.3, 126.7, 125.9, 119.1, 118.0, 110.0, 108.6, 78.5, 29.3, 28.5, 28.0, 26.4, 23.5, 21.2; IR (diffuse reflectance) 1684, 1481, 1448, 1398, 1378, 1364, 1357, 1304, 1184, 1149 (s), 1103, 732, 690, 622, 612 cm−1; HRMS (FAB) calcd for C25H30N2O4S+H 455.2004, found 455.2027; Anal. Calcd for C25H30N2O4S: C, 66.05; H, 6.65; N, 6.16. Found: C, 65.99; H, 6.66; N, 6.19.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([SH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[CH:16]12[O:21][CH:20]1[CH2:19][O:18][CH2:17]2>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@@H:20]2[CH2:19][O:18][CH2:17][C@H:16]2[OH:21])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: C1OCC2OC12
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
3,5-Bis(1,1-dimethylethyl)benzenethiol (0.0078 mole) and the title compound of Example 18 (0.0074 mole) are added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction is heated to reflux for 24 hours. The reaction is cooled to room temperature and poured into water (125 ml). The solution is made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts are dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator. The product is purified by silica gel chromatography.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone 0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>>[F:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][CH2:17][CH2:16][NH:12][CH2:13][CH2:14][O:11]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: OCCNCCO
Product: Fc1cc(F)cc(B2OCCNCCO2)c1
Yield: 93 %

Procedure:
The title compound (93%, crystals) was prepared from 3,5-difluorophenylboronic acid and diethanolamin.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=O)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na+].[Cl-]>ClCCCl.C(O)(=O)C>[CH3:14][N:15]([CH2:12][C:10]1[N:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1cn(-c2ccccc2)nn1
Reactant: CNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1cn(-c2ccccc2)nn1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde, 9, (0.23 g, 1.35 mmol) in 1,2-dichloroethane (2 mL) was added N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.20 g, 1.23 mmol), sodium triacetoxyborohydride (0.10 g, 1.60 mmol), and 3 drops of acetic acid. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then poured into aqueous saturated NaCl (10 mL) and was extracted with ethyl acetate (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 35 mg (9%) of Y: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.78, (d, J=8.4 Hz, 2H), 7.50-7.39, (m, 4H), 7.20, (m, 1H), 4.72, (d, J=13.6 Hz, 1H), 4.63-4.58 (m, 2H), 2.90-2.60 (m, 6H), 2.22-2.17 (m, 1H), 2.10-1.95, (m, 1H), 1.90-1.78, (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[S:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:33])=[O:32]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([S:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:33])=[O:32])[CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)cn1
Reactant: COC(=O)CCS(=O)(=O)Cl
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5cnc(C)cn5)CC4)sc3c2)CC1

Procedure:
Compound 50D was prepared from Compound 50C and methyl 3-(chlorosulfonyl)propanoate in a similar manner to the procedure described for Compound Example 16.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(OC1CC=CC1)(=O)=O>CN(C)C=O>[CH:23]1([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[CH2:24][CH:25]=[CH:20][CH2:26]1
Reactant: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Reactant: Cc1ccccc1
Agent: CS(=O)(=O)OC1CC=CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C1=CCC(n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.32 g, 5.29 mmol) was azeotroped with toluene and placed under high vacuum for 30 min. N,N-Dimethylformamide (17.7 mL) was added, followed by cesium carbonate (1.99 g, 6.10 mmol). The mixture was stirred at 70° C. for 10 min. Cyclopent-3-en-1-yl methanesulfonate (0.660 g, 4.07 mmol) in N,N-dimethylformamide (12.6 mL) was added dropwise. The reaction mixture was heated to 110° C. for 1 h. The reaction mixture was cooled, quenched with brine and diluted with H2O. The aqueous layer was extracted with EtOAc (3×), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by via silica gel chromatography, eluting with a gradient of 0 to 5% MeOH in DCM followed by 25 to 50% EtOAc in hexanes, to afford the title compound as a pale brown solid (0.684 g, 53%). LC/MS: Rt=1.38 min, ES+ 317 (FA standard).