Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:5])[CH3:4].[N:20]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C1CCc2[nH]c3ccccc3c2C1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C1CCc2c(c3ccccc3n2CCN2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1.20g; 50% dispersion in oil) was added to a solution of 3-tert-butyl-1,2,3,4-tetrahydrocarbazole (5.68g) in dry dimethylformamide (25ml) and the mixture was heated over a steam bath for 1/2 hour. 2-Pyrrolidinoethyl chloride (3.34g) was then added, and the mixture was heated over the steam bath for a further 4 hours. Thereafter the mixture was cooled at room temperature, allowed to stand for about 16 hours, and poured into water. The aqueous mixture was extracted with diethyl ether, and the ethereal solution was evaporated in vacuo to afford 3-tert-butyl-9-(2-pyrrolidinoethyl)-1,2,3,4-tetrahydrocarbazole as an oil. The latter was distilled under reduced pressure, the principal fraction collected having a b.p. of 185°-195°C/0.05mm. mercury pressure.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=[O:7]>CN(C=O)C>[Cl:3][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C:9]=1[CH:6]=[O:7]
Reactant: O=C(O)COc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1oc2ccccc2c1Cl
Temperature: 25 °C
Yield: 25.6 %

Procedure:
To a cooled solution of phosphorus oxychloride (19 mL, 209 mmol) in DMF (40 mL) is slowly added 2-carboxymethoxybenzoic acid (6.84 g, 35 mmol) in portions. The mixture is warmed to room temperature for 30 min and then heated to 90° C. overnight. The mixture is cooled to room temperature and poured carefully into ice water, extracted with ethyl acetate (3×50 mL), dried with sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, hexanes/ethyl acetate, 4:1) gave title compound (1.62 g, 26%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.82-7.88 (m, 2H), 7.69-7.73 (m, 1H), 5.51-7.56 (m, 1H).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C(=C)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.C=[C:30]1[CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@H:32]([C@H:33]3[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]3)[CH2:31]1>>[CH2:1]=[C:31]1[CH2:30][CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@@H:32]1[C@H:33]1[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Product: C=C1CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 87 %

Procedure:
The title compound II-aw was prepared in 87% yield from 3,3:17,17-bis(ethylendioxy)-7-methyleneandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (I-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.70 (1H, m), 4.62 (1H, m), 2.20-1.10 (20H, m), 1.00 (3H, s), 0.88 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
At 0° C., 859 ml (859 mmol) of a 1 M solution of boran/tetrahydrofuran complex in tetrahydrofuran are added dropwise to 110 g (573 mmol) of 5,6-dichloro-nicotinic acid in 250 ml of tetrahydrofuran. The mixture is warmed to room temperature and stirred at this temperature for 3 hours. After cooling to 0° C., the reaction mixture is made alkaline using saturated aqueous potassium carbonate solution, most of the tetrahydrofuran is removed using a rotary evaporator and the residue is extracted repeatedly with ethyl acetate. The combined organic phases are washed with water and saturated in aqueous sodium chloride solution and dried over sodium sulphate. The organic phase is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the molar phase mixture ethyl acetate:cyclohexane (1:2), giving 62 g (61% of theory) of (5,6-dichloropyridin-3-yl)methanol.
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[CH:13]([OH:14])[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:15]([N:9]1[CH2:10][CH:11]2[CH:13]([O:14][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]([CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12]2)[CH2:8]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN1CC2CN(CCCC)CC(C1)C2O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCCCN1CC2CN(CCCC)CC(C1)C2OC(=O)c1ccc(Cl)cc1
Yield: 57.5 %

Procedure:
10.18 g of 3,7-di-n-butyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are reacted with 7.7 g of 4-chloro-benzoyl chloride as described in Example 8 to obtain 3,7-di-n-butyl-9-(4'-chlorobenzoyloxy)-3,7-diazabicyclo[3.3.1]nonane, which is converted into its fumarate. The salt, melting at 180°-181° C., is obtained with a yield of 57.5%.
Reaction SMILES: Cl[CH:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:14].[CH:15]([Mg]Cl)=[CH2:16].CN1C(=O)N(C)CCC1.[Cl-].[NH4+]>C1COCC1>[CH:15]([C:4]12[O:14][CH:3]1[CH2:2][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH2:16]
Reactant: C=C[Mg]Cl
Reactant: O=C1CCCCCCCCCCC1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C=CC12CCCCCCCCCCC1O2
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A four-neck flask equipped with a thermometer, stirrer and condenser tube was charged with 100 g (0.46 mol) of 2-chlorocyclododecanone and 122 g of tetrahydrofuran, and at −10 to 0° C., a THF solution of vinylmagnesium chloride (0.82 mol) was added dropwise. The mixture was allowed to stand for reaction for 30 minutes, and 420 g (3.27 mol) of N,N′-dimethylpropyleneurea (DMPU) was added. The mixture was heated to 50° C. and allowed to stand for reaction for 1 hour, and saturated ammonium chloride aqueous solution was added dropwise for inactivation. The reaction mixture was subjected to extraction with hexane, and the solvent was recovered. The residue was distilled to obtain 1-vinyl-13-oxabicyclo[10.1.0]tridecane (80 g, 0.38 mol, chemical purity 98%, cis form:trans form=88:12). The yield was 82%.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[N:19]=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:16][CH:15]=1>>[Br:13][C:14]1[N:19]=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1cccc(Br)n1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cccc(Br)n1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (42.1 mL, 35.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (23.6 mL, 35.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(6-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (3.2 g, 11.8 mmol, in tetrahydrofuran 30.0 mL) prepared in Step 2 was slowly added at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 2.4 g of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24]>CS(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
142 mg (1 mmol) of 2,4-difluorobenzaldehyde were dissolved in 5 ml DMSO and taken and combined with 200 mg (1.45 mmol) of K2CO3. 128 mg (1 mmol) of 2-chlorophenol were dissolved in 10 ml DMSO and added and stirred for 2 days at ambient temperature. The reaction mixture was filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The substance was purified by reversed-phase chromatography.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[C:31]3[N:32]=[C:15]([CH:16]=[CH:17][N:18]3[N:19]=[CH:20]1)[N:14]1[C@@H:10]2[CH2:11][CH2:12][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24][N:23]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C:21]1=[C:31]3[N:32]=[C:15]([CH:16]=[CH:17][N:18]3[N:19]=[CH:20]1)[N:14]1[C@@H:10]2[CH2:11][CH2:12][CH2:13]1
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Methanesulfonyl chloride (1.69 μL, 0.0218 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaene (Example 24, 4.0 mg, 0.0109 mmol), followed by DIEA (9.48 μL, 0.0544 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to afford the title compound (2.9 mg, 59.8% yield). MS (apci) m/z=446.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C@H:9]([C:11](=[O:41])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:54])(=O)[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:16]=3[N:15]([C:48](=[O:50])[C:47]3[CH:46]=[CH:45][C:44]([C:43]([N:15]4[C:16]5[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:42])[CH3:8])[CH3:10])[CH2:14]4)=[O:54])=[CH:52][CH:51]=3)[CH2:14][C@H:13]([NH:12][C:11](=[O:41])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:42])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.5 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-cyano-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 4) (120 mg, 0.189 mmol) in pyridine (2 mL) was added terephthalic acid (20.604 mg, 0.113 mmol). After 10 min, the mixture was cooled to 0° C., POCl3 (0.036 mL, 0.396 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-5-[4-[(3S)-1-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (6 mg, 1%) as an off white solid. LC-MS: 1403.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 1 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 88% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.89 min (98.61%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 1.42 (t, J=7.1 Hz, 3H, CH3), 1.96-2.14 (m, 1H, CHH), 2.42-2.69 (m, 2H, CHH, CHH), 2.78-3.01 (m, 1H, CHH), 4.58 (q, J=7.0 Hz, 2H, CH2), 4.68 (d, J=6.2 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.35 (d, J=9.1 Hz, 1H, Ar), 7.76-7.95 (m, 3H, Ar), 8.09 (d, J=9.1 Hz, 1H, Ar), 9.85 (t, J=6.2 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 21.99, 30.93, 42.39, 48.99, 63.47, 117.91, 122.10, 123.53, 128.83, 129.82, 131.59, 133.57, 147.30, 149.11, 162.93, 165.86, 166.99, 167.13, 169.83, 172.75; LCMS: MH=438; Anal Calcd for C21H19N5O6: C, 57.66; H, 4.38; N, 16.01. Found: C, 57.32; H, 4.16; N, 15.80.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH:49]2[CH3:54])=[N:44][CH:45]=[N:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][N:46]=[CH:45][N:44]=3)[CH:49]([CH3:54])[CH2:50]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cncnc1N1CCNCC1C
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCc2csc3ccccc23)CC1C

Procedure:
The title compound was prepared (0.20 g, 24%, mp 140°-144° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(5-methoxy-4-pyrimidinyl)-2-methylpiperazine.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[CH3:31]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH3:31])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Reactant: CI
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(C)c3=O)cc1-2
Yield: 20 %

Procedure:
Following the procedure for 477, compound 330 and iodomethane were reacted to give 502 (0.039 g, 20%). 1H NMR (500 MHz, DMSO) δ 9.05 (d, J=2.3, 1H), 8.09 (s, 1H), 7.73 (dd, J=6.7, 1.9, 1H), 7.66 (ddd, J=10.7, 7.7, 2.1, 2H), 7.07 (d, J=8.4, 1H), 6.34 (t, J=6.8, 1H), 5.94 (dt, J=13.2, 6.6, 1H), 4.40 (t, J=4.9, 2H), 3.53 (s, 3H), 3.46 (t, J=5.0, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=2)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:28]([C:30]1[CH:31]=[C:32]([NH:36][C:37]([C:39]2[N:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)#[CH:29]>>[C:23]([O:22][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([CH3:13])(=[O:12])=[N:10][C:8](=[O:9])[C:4]2[CH:3]=[C:2]([C:29]#[C:28][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[N:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=4)=[O:38])[CH:31]=3)[CH:7]=[N:6][CH:5]=2)=[CH:15][CH:16]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)cc1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(NC(=O)OC(C)(C)C)cc4)c3)c2)n(C)n1
Yield: 336.4 %

Procedure:
In a manner similar to that described in Example 460, tert-butyl (4-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)carbamate (0.158 g, 0.349 mmol) and 2,5-dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide (0.125 g, 0.0524 mmol) were reacted to give the title compound (0.108 g, 51%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1[CH2:45][CH2:44]OCC1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[N:20][C:21]([N:16]3[CH2:45][CH2:44][NH:22][CH2:23][CH2:18]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCO1
Reactant: Cc1ccccc1Oc1nc(S(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1Oc1nc(N2CCNCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 132.3 %

Procedure:
To a solution of 0.30 g (0.52 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyloxy-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0.112 g (1.3 mmol) piperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml sat. NaHCO3-solution. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.20 g (66%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 582.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][O:21]2)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Yield: 96.2 %

Procedure:
2-(Benzyloxy)-5-(2-bromoacetyl)benzamide (11.3 g, 32.30 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL) and cooled in an ice bath. The solution was diluted with ethanol (250 mL). Sodium borohydride (1.2 g, 32.3 mmol) was added in three portions. Following addition the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield crude title compound (1 0.88 g, 31.06 mmol).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2>C(O)C>[CH:1]1([NH:6][C:17]2[C:16](=[O:19])[C:15]3[C:10]([C:9](=[O:20])[C:8]=2[Cl:7])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: NC1CCCC1
Solvent: CCO
Product: O=C1C(Cl)=C(NC2CCCC2)C(=O)c2ccccc21
Temperature: 25 °C

Procedure:
18.7 G. of cyclopentylamine in 50 ml. of absolute ethanol are added dropwise while stirring at room temperature to a suspension of 22.7 g. of 2,3-dichloro-1,4-naphthoquinone in 100 ml. of absolute ethanol. After the addition, the mixture is boiled under reflux for 1 hour. The resulting dark-red mixture is then evaporated under reduced pressure. The residue is then dissolved in 600 ml. of chloroform and shaken out successively with 200 ml. of water, three times with 100 ml. of 3-N hydrochloric acid each time and three times with 100 ml. of water each time. After drying over sodium sulfate, the chloroform solution is concentrated, treated with active carbon and evaporated. After crystallization from n-hexane, 23.9 g. of 2-cyclopentylamino-3-chloro-1,4-naphthoquinone of melting point 81°-83°C. are obtained.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][NH:8][CH:9]=[O:10]>[Cu]I>[CH3:7][N:8]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH:9]=[O:10]
Reactant: CNC=O
Reactant: Brc1ccsc1
Agent: [Cu]I
Product: CN(C=O)c1ccsc1
Yield: 81 %

Procedure:
Using general procedure C with the exception that CuI (10 mg, 0.05 mmol, 5 mol %) was used, 3-bromothiophene was coupled with N-methylformamide with the reaction time of 24 h. Chromatography gave 114 mg (81%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz): δ 8.36 (s, 0.8H), 7.71 (s, 0.2H), 7.49 (dd, 0.2H, J=1.5, 5.4 Hz), 7.08 (dd, 0.2H, J=1.2, 3.0 Hz), 6.80 (dd, 0.2H, J=3.3, 5.4 Hz), 6.64 (dd, 0.8H, J=3.3, 5.1 Hz), 6.30 (dd, 0.8H, J=1.8, 5.4 Hz), 5.98 (dd, 0.8H, J=1.2, 3.0 Hz), 2.79 (s, 2.4H), 2.21 (s, 0.6H).