Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[C:3]=1[F:19].C(Cl)(=O)C(Cl)=O.[CH3:26][N:27](C=O)C.Cl.CN.C(N(CC)CC)C>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH3:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[C:3]=1[F:19]
Reactant: CN(C)C=O
Reactant: Cc1nccc(-c2ccc(Br)c(F)c2F)c1C(=O)O
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 409.3 %

Procedure:
To a solution of 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinic acid (700 mg, 2.13 mmol) in dichloromethane (20 mL) at 0° C. was added oxalyl chloride (0.56 mL, 6.40 mmol) drop wise followed by DMF (0.03 mL, 0.43 mmol). The reaction mixture was heated to 45° C. for 4 h. The reaction mixture was evaporated to dryness. The residue was taken in dichloromethane (50 mL) at 0° C. and methylamine hydrochloride (1.56 g, 23.08 mmol) was added to it followed by triethylamine (4.83 mL, 34.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-bromo-2,3-difluorophenyl)-N,2-dimethylnicotinamide (600 mg, 1.76 mmol, 76% crude yield) as yellow semi-solid which was carried on without further purification. LC/MS (ESI) m/e 343.0 [(M+2H)+, calcd for C14H13BrF2N2O 343.0]; LC/MS retention time (method C): tR=1.61 min.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([Li])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl.CCCCCC>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(C(O)CCCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (Example 1) and butyllithium according to the procedures described in Example 114. 1H NMR (300 MHz, CDCl3): δ 6.95 (m, 4 H), 4.33 (m, 1 H), 3.59 (septet, J=6.6 Hz, 1 H), 3.09 (septet, J=6.6 Hz, 1 H), 2.08 (t, J=5.2 Hz, 2 H), 1.75 (m, 2 H), 1.47 (m, 2 H), 1.04 (m, 22 H), 0.719 (t, J=7.0 Hz, 3 H), 0.674 (t, J=7.0 Hz, 3 H). FAB-MS: calcd for (C27H40FNO) 413, found 414 (M+H). Anal. Calcd for C27H40FNO: C, 78.41; H, 9.75; N, 3.39; F, 4.59. Found: C, 77.84; H, 9.51; N, 3.27; F. 5.08. mp 66-68° C. Rf=0.2 (50% CH2Cl2/hexane).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCc2ccc3ncccc3c2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc4ncccc4c3O2)cc1
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A solution of (6S)-(7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.14 g, 0.65 mmole) and p-toluenesulfonyl chloride (0.25 g, 1.3 mmole) in anhydrous pyridine (50 mL) was allowed to stir for 24 hours and then the solvent was removed in vacuum. The residue was dissolved in ethyl acetate (50 mL) and washed with water (3×30 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (50% methylene chloride/hexane) afforded 0.23 g (96%) of the title compound as a solid, mp 123° C., [α]25D=+51.22° (4.92, CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)[CH3:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1csc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCc1c(Cl)sc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 1 h

Procedure:
A solution of 7-ethylthieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 5.1 mmol) in 250 ml of acetic acid was stirred in a dry nitrogen atmosphere and sulphuryl chloride (0.41 ml, 5.1 mmol) was added dropwise. Stirring was continued for 1 h, the precipitate was filtered off, washed with water and dried at 100° C. under reduced pressure (30 Torr). Yield 0.77 g (65%) of the title compound. M.p. 282°-284° C. 1H-NMR (DMSO-D6, δ): 1.05 (t, 3H), 2.65 (q, 2H), 12.02 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:27])[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:9]=2)=[O:4].CO.[Li+].[OH-]>C1COCC1>[C:23]([CH:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:15]([C:10]2[CH:9]=[C:8]3[C:13]([CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[C:7]3[CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:12][CH:11]=2)=[O:27])[CH2:22][CH2:21]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Yield: 118.2 %

Procedure:
A solution of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester (57 mg, 0.126 mmol) in THF:MeOH was treated with an aq. solution of LiOH (26 mg, 0.632 mmol) via the general procedure I to give 65 mg of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid. This was used directly for the next step.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: CC(=O)NCCc1nc(C(=O)N2CCc3c(ccc(C)c3O)C2)c2ccccc2n1
Yield: 7 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 78 (7% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 and 1.76 (2s, 3H), 2.12 and 2.16 (2s, 3H), 2.62 and 2.88 (2t, 2H), 3.12-3.20 (m, 2H), 3.48 and 4.00 (2t, 2H), 3.54-3.64 (m, 2H), 4.35 and 4.88 (2s, 2H), 6.31 and 6.72 (2d, 1H), 6.80 and 6.98 (2d, 1H), 7.72-7.92 (m, 3H), 8.01-8.06 (m, 2H), 8.34 and 8.42 (2s, 1H); MS (ESI) m/z 405 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (20.1 g, 48.6 mmol) in EtOAc (200 mL) was added 4 M hydrogen chloride in EtOAc (200 mL). The mixture was stirred at ambient temperature for 90 min and concentrated to give a solid. The solid was alkalized with saturated aqueous NaHCO3 (pH=9), concentrated, and purified by flash chromatography (NH silica gel, 33% MeOH in CHCl3) to give trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (14.7 g, 97%) as a white solid.
Reaction SMILES: [H][H].C([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]([F:21])=[C:19]([C:22]3[C:23]([O:37][CH:38]4[CH2:41][CH2:40][CH2:39]4)=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][CH3:35])=[O:33])[C@@H:27]([CH3:36])[CH2:26][CH2:25]4)[CH:18]=[N:17]2)[CH2:12][CH2:11]1)C1C=CC=CC=1.[3H][3H]>CO.[OH-].[OH-].[Pd+2]>[CH:38]1([O:37][C:23]2[C:22]([C:19]3[CH:18]=[N:17][N:16]([CH:13]4[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]4)[C:20]=3[F:21])=[CH:31][CH:30]=[C:29]3[C:24]=2[CH2:25][CH2:26][C@H:27]([CH3:36])[N:28]3[C:32]([O:34][CH3:35])=[O:33])[CH2:39][CH2:40][CH2:41]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(Cc5ccccc5)CC4)c3F)c(OC3CCC3)c2CC[C@@H]1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [3H][3H]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3F)c(OC3CCC3)c2CC[C@@H]1C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Balloon filled hydrogen was charged into a nitrogen purged suspension of (S)-methyl 6-(1-(1-benzylpiperidin-4-yl)-5-fluoro-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (15.0 mg, 0.028 mmol) and 20% palladium hydroxide on carbon (40 mg, 0.285 mmol) in methanol (10 mL). The reaction flask was backfilled with hydrogen 3 times. The reaction solution was then stirred under a hydrogen atmosphere for 2 hours. The flask was purged with nitrogen, and the reaction mixture was filtered through of Celite and the bed of Celite was washed with ethyl acetate (10 mL). The filtered solvent was then concentrated in vacuo. The crude product was added directly to a plug of silica gel and eluted with 30% ethyl acetate in methanol to afford methyl (S)-5-cyclobutoxy-6-(5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (7.2 mg, 58%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (d, J=6.45 Hz, 3H), 1.21-1.30 (m, 2H), 1.42-1.57 (m, 1H), 1.76-1.88 (m, 3H), 1.89-2.01 (m, 5H), 2.34-2.43 (m, 2H), 2.53-2.61 (m, 1H), 2.71-2.85 (m, 2H), 3.03 (br d, J=12.31 Hz, 1H), 3.13-3.21 (m, 1H), 3.68 (s, 3H), 3.95-4.05 (m, 1H), 4.15-4.30 (m, 1H), 4.41-4.52 (m, 1H), 7.14 (d, J=8.15 Hz, 1H), 7.29 (d, J=8.79 Hz, 1H), 7.61 (s, 1H). MS (ESI, pos. ion) m/z 443 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To 2.00 g of ethyl 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylate were added 10 ml of ethanol and 20 ml of 10% aqueous sodium hydroxide solution, followed by stirring at room temperature for an hour. To the reaction solution was added dropwise 3 N hydrochloric acid to make acidic (pH=3.0), and the precipitated crystals were collected by filtration and washed with water and diethyl ether to give 1.73 g of 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:9][CH:8]=[CH:7][S:6]1.O>CO>[N:13]1[CH:12]=[CH:11][C:10]([C:5]2([CH2:4][C:3]([OH:16])=[O:2])[NH:9][CH:8]=[CH:7][S:6]2)=[CH:15][CH:14]=1
Reactant: COC(=O)CC1(c2ccncc2)NC=CS1
Solvent: O
Solvent: CO
Product: O=C(O)CC1(c2ccncc2)NC=CS1
Temperature: 75 °C

Procedure:
In a 100-mL, round-bottomed flask was placed 2-(4-pyridyl)-thiazole acetic acid methyl ester (Step a, 818 mg, 3.5 mmol), LiOH monohydrate (154 mg, 3.67 mmol) in MeOH (20 mL), and H2O (2 mL). The solution was heated to 75° C. for 2 h, cooled to RT, and concentrated. The resulting yellow solid was dissolved in H2O (10 mL) and extracted with EtOAc (15 mL). The aqueous layer was acidified with 1N aqueous HCl (3.67 mL). The resulting precipitate was filtered, and washed with H2O (10 mL) to afford 2-(4-pyridyl)-thiazole acetic acid as a light yellow solid. Mp: >240° C. MS m/z: 221 (M+1). Calc'd for C10H8N2O2S: 220.03.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=4)[CH:20]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]3[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=4)[CH:20]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c([N+](=O)[O-])cn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c(N)cn2)c1

Procedure:
The product from Step 2 (2.7 g, 5.2 mmol) was dissolved in MeOH (20 mL), Pd/C (5% on C, 100 mg) was added the mixture was hydrogenated with a balloon of hydrogen for 2 days, then filtered through celite. The filtrate was concentrated to give the title compound which was taken on without purification. MS (ES+) m/e 491 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccsc1CBr
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
2-Methyl-3-cyanothiophene (2.108 g) was dissolved in benzene (30 ml), followed by the addition of N-bromosuccinimide (4.8 g) and 70% benzoyl peroxide (202 mg), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled, and the resulting precipitates were filtered off. Then the filtrate was diluted with ethyl acetate, washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and then evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (2.746 g, yield; 82%).
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:11])[CH2:5][C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2].N12CCN(CC1)CC2.[C:20]1(=[O:25])[CH2:24][CH2:23][CH:22]=[CH:21]1>COCCOC>[CH2:1]([S:3][C:4](=[O:11])[CH:5]([CH:22]1[CH2:23][CH2:24][C:20](=[O:25])[CH2:21]1)[C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCSC(=O)CC(=O)SCC
Reactant: O=C1C=CCC1
Agent: C1CN2CCN1CC2
Solvent: COCCOC
Product: CCSC(=O)C(C(=O)SCC)C1CCC(=O)C1
Yield: 86.8 %

Procedure:
A solution of dithiomalonic acid di-S-ethyl ester (42.3 g, 0.22 mol) and 1,4-diazabicyclo[2,2,2]octane (24.7 g, 0.22 mol), cyclopent-2-enone (17.6 g, 0.21 mol) in 1,2-dimethoxyethane (300 mL) was stirred at room temperature under nitrogen for 48 h. The mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% ethyl acetate/pentane) afforded 2-(3-oxo-cyclopentyl)-dithiomalonic acid di-S-ethyl ester as a white solid (50.0 g, 82%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[S:5][CH:6]=1.CC1(C)C(C)(C)OB([C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)O1>>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]2[CH:23]=[C:22]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]4)[S:5][CH:6]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: O=C1CCN(c2nc(Br)cs2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described via a Suzuki reaction starting from 339 mg (1.18 mmol) of 1-(4-bromothiazol-2-yl)piperidin-4-one (preparation already described above) and 449 mg (1.30 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:14]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][N:6]=1)#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccnc(C#N)c1
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[C:40](/[CH2:46]N2C=CC=N2)=[CH:41]\[C:42](OC)=[O:43])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])/[CH:41]=[C:40](/[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)\[CH3:46])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C(/Cn1cccn1)c1cccc(C#N)c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (105 mg, 0.34 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.5 ml, 1.02 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of methyl (E)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (90 mg, 0.34 mmol) in 1 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (155 mg, 85%) as an off-white foam which was sufficiently pure to be used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([C@@H:30]([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@@H:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@@H](Cc1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N[C@@H](Cc1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
The title compound was prepared in a yield of 92% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and (S)-1,2-diphenylethylamine.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.S(Cl)(Cl)=O.C(OC1C=CC(CO)=CC=1)CCCCCCCCC>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCOc1ccc(CCl)cc1
Agent: CCCCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCOc1ccc(CCl)cc1

Procedure:
Was synthesized following the same general procedure as that for the preparation of 4-dodecyloxybenzyl chloride; thionyl chloride (5.00 g, 42.4 mmol), 4-decyloxybenzyl alcohol (10.2 g, 38.6 mmol), CH2Cl2 (100 mL). 9.87 g (90%) white solid which decomposes upon melting.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and morpholine (10 μl, 0.11 mmol), and stirred 18 hours at room temperature. The reaction was heated to 50° C. for 8 hours, and then was allowed to stir 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-morpholinoethoxy)benzamide. MS (Q1) 530 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
48.6 G. of 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester are dissolved in 750 ml. of glacial acetic acid. 18.9 G. of sodium borohydride are added in small portions within 20 minutes with stirring and cooling in such a manner that the temperature does not exceed 25° C. The mixture is stirred for an additional 30 minutes at 25° C. and then the glacial acetic acid is removed by distillation in vacuo. The residue is partitioned between chloroform and aqueous sodium hydroxide solution. The organic phase is separated and washed with water. The aqueous phases are extracted two additional times with chloroform. The combined chloroform extracts are dried over sodium sulfate, evaporated in vacuo, and there is obtained crude 4-[10,11-dihydro-2,8-dimethyldibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.