Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:24][C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ncccc2Cl)CC1
Yield: 34.4 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 2,3-dichloropyridine (173 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (74 mg), a beige solid, in 34% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[NH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:14][NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(N)=O
Reactant: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC=C(C(=O)OCC)c1ccc(Cl)cc1
Yield: 73.4 %

Procedure:
Then, 14.2 g of ethyl p-chlorophenyl-(α-formyl)acetate and 6.5 g of urethane were added to 50 ml of toluene containing 0.3 ml of concentrated sulfuric acid, and the mixture was heated at reflux while distilling out water which was formed during the reaction until no further water was distilled out. Thereafter, the solvent was distilled off, and the residue was extracted with diethyl ether while hot. The solvent was distilled off from the extract to obtain 13.7 g of ethyl p-chlorophenyl-(α-ethoxycarbonylaminomethylene)acetate having a melting point of 72° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O>>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCc1[nH]nc(N)c1C#N
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
As for Example 1, 3-amino-5-ethylpyrazole-4-carbonitrile is reacted with 3-dimethylamino-3'-(trifluoromethyl)-acrylophenone to give the product as crystals, m.p. 144°-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:12][OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: CCOc1cc(CO)c(Br)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1cc(C=O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-5-ethoxy-4-methylphenyl)methanol (2.30 g, 9.38 mmol) in DCM (40 mL) was added Dess-Martin periodinane (5.97 g, 14.08 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether and was then concentrated. The residue was taken up in ether and was washed with of a mixture of 10% aqueous Na2S2O3 and saturated aqueous NaHCO3 (1/1), water and brine. The aqueous washings were back-extracted with ether and the organic layer was washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to afford the title intermediate as a white solid
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:38])[NH:32]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:37][C:36]4[C:28]([F:27])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:38])=[CH:30]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (20.0 g, 52.3 mmol), 4-fluoro-5-hydroxy-2-methylindole (10.5 g, 63.3 mmol), (prepared as described for the starting material in Example 1), and cesium carbonate (34.4 g, 106 mmol) in acetone (500 ml) was heated at reflux for 4 hours. The mixture was cooled and allowed to stand overnight. The mixture was filtered and the solid suspended in water and re-filtered and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5) to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (20.4 g, 77%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:42]([O:44]C(C)(C)C)=[O:43])[NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:42]([OH:44])=[O:43])[NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:30])=[O:31])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCc1c(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1c(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 82 %

Procedure:
220 mg (0.33 mmoles) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulphonyl)alaninate in 20 ml of dichloromethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 230 mg (Yield=82% expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8](C=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCCN
Reactant: CCCCc1ccc(C=O)cc1
Agent: Cl
Product: CCCCc1ccc(NCCCCCCC(=O)OC)cc1
Yield: 42.4 %

Procedure:
Following the procedure described in Step A of Example 68, reductive amination of 4-butyl-benzaldehyde (1.50 g, 9.26 mmol) with 7-aminoheptanoic methyl ester hydrochloride (1.51 g, 7.72 mmol) provided the title compound (955 mg). 1H NMR (300 MHz, CDCl3) δ 7.29 (d, 2H), 7.16 (d, 2H), 3.85 (s, 2H), 3.67 (s, 3H), 3.54 (m, 1H), 2.70 (t, 2H), 2.59 (t, 2H), 2.29 (t, 2H), 1.60 (m, 6H), 1.32 (m, 6H), 0.92 (t, 3H); MS 306 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11][C:10]1([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[CH:42]=1)[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:63](Cl)(=[O:65])[CH3:64].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl.C(OC(=O)C)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][C:10]1([O:40][C:63](=[O:65])[CH3:64])[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][C:48]2[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)[CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cc2cccc(C3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2cccc(C3(OC(C)=O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2R,3S,4R,5R]-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[3-(4-methoxybenzyl)phenyl]cyclohexanol (20 mg), triethylamine (0.008 mL) and 4-dimethylamino-pyridine (0.7 mg) in dichloromethane (0.10 mL), acetic anhydride (0.003 mL) was added under cooling with ice and the reaction mixture was stirred at room temperature for two hours. Then, acetyl chloride (0.003 mL) was added thereto under cooling with ice and the reaction mixture was stirred at room temperature for 30 minutes. a saturated sodium hydrogen-carbonate aqueous solution was added thereto and the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by preparative TLC [developing solution=ethyl acetate:n-hexane (2:5)] to obtain the title compound (4.2 mg).
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[CH:17]([CH2:22][CH2:23][Br:24])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:10]1([CH:8]([C:3]([C:1]#[N:2])([C:4]([O:6][CH3:7])=[O:5])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH2:23][Br:24])[CH3:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(C#N)C(C)c1ccccc1
Reactant: COC(=O)C(Br)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCBr)C(C#N)(C(=O)OC)C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-cyano-3-phenylbutyrate (78 g, 0.37 mole), methyl 2,4-dibromobutyrate (122 g, 0.47 mole), potassium carbonate (65 g, 0.47 mole) and DMSO (50 ml) was stirred on a ball mill apparatus. The reaction was completed in four hours. Ice water was added and the mixture was neutralized by adding cold hydrochloric acid. The aqueous solution was extracted several times with ether. The combined organic solution was washed sequentially with cold aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was purified by Kugelrohr distillation (100° C., 30 microns) to remove low boiling materials. The remaining oily residue (118 g., 84%) was found to be mainly the title bromide condensation product (ν<95% GC purity). MS m/e (% relative intensity) 383(M.+, 3) 381 (3), 202 (33), 182 (7), 180 (7), 105 (100).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][P:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:14]=1)([CH3:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([P:10]([CH3:12])([CH3:9])=[O:11])=[CH:14][C:15]=2[S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (1.31 mmol) in 1 mL of DMF is added 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: (1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at 110° C. until formation of the desired compound. The reaction mixture is basified with saturated sodium bicarbonate solution. The suspension is filtered and washed with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:36])=[CH:8][C:9](=[O:35])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][S:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([O:29]C)=[O:28])[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:36])=[CH:8][C:9](=[O:35])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][CH2:22][CH2:23][S:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([OH:29])=[O:28])[CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1SCCNC1CCN(CCn2c(=O)cc(C)c3ccc(OC)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCCSc4ccccc4C(=O)O)CC3)c2c1
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To 1 mL of an ethanol solution containing 60 mg of methyl 2-((2-(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-ylamino)ethyl)thio)benzoate, 0.1 mL of 20% aqueous sodium hydroxide solution was added at room temperature and stirred for 1 hour and 40 min. After the solvent was removed from the reaction mixture under reduced pressure, water was added, adjusted to pH 6.2 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered, washed with water and diethylether to give 28 mg of 2-((2-(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-ylamino)ethyl)thio)benzoic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 110.0 g. (0.62 mole) of 3'-acetylacetanilide in 2400 ml. of chloroform is added dropwise a solution of 33.0 ml. (102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred one hour and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol. The dried product weighs 148.34 g., and is recrystallized from 2-propanol to give the product, melting point 108.5°-110°C. Analysis: Calcd. for C10H10BrNO2 : Calcd: C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C, 47.12; H, 3.94; Br, 31.21; N, 5.47.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].N1C=CC=CC=1.[SH2:15]>C(N(CC)CC)C>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]([NH2:7])=[S:15]
Reactant: S
Reactant: CN(C)CCCC#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(C)CCCC(N)=S
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A reaction mixture was prepared containing 95.2 g. of 4-dimethylaminobutyronitrile, 134.3 g. of pyridine, 257.6 g. of triethylamine and 113 g. of H2S. The reaction mixture was placed in an autoclave and the autoclave shaken for about 16 hours at 55° C. The reaction mixture was then removed from the autoclave and the volatile constituents removed by evaporation in vacuo. The resulting residue comprising 4-dimethylaminothiobutyramide formed in the above reaction was digested with about 1.5 l. of boiling ethyl acetate. The mixture thus produced was filtered through cellulose (hyflo supercel). The filtrate was concentrated until crystals appeared. The crystals were separated by filtration and the separated crystals washed with ethyl acetate. Sixty grams of 4-dimethylaminothiobutyramide melting at about 77° C. were obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]1([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Li]>C(Cl)Cl.CCOCC>[C:7]1([CH2:13][C:14]2[CH:15]=[CH:19][CH:20]=[CH:21][C:22]=2[C:1](=[O:5])[CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Oxalyl chloride (4.1 ml, 47 mmol) was added to a solution of 2-(phenylmethyl)benzoic acid (from Aldrich) in methylene chloride (100 ml) over 5 minutes at room temperature. The solution was allowed to stir at room temperature for 2 hours. The solution was concentrated and the resultant orange gum azeotroped with benzene (twice) and placed under high Vacuum for 1 hour. In a separate flask, methyl lithium (1.4M in THF, 100 ml, 140 mmol) was added over 10 minutes to a slurry of CuI2 (13.432 gm, 42.3 mmole) in ether (125 ml). The slurry was allowed to stir for 2 minutes. The above-prepared acid chloride in ether (50 ml) at -78° C. was cannulated over 20 minutes into the dimethyl lithiumcuprate solution, which was also cooled to -78° C. The solution stirred for an additional 20 minutes, then was quenched with methanol (30 ml) and warmed to room temperature. The solution was then added to saturated NH4Cl (200 ml), and the aqueous layer was extracted with ether (twice). The organic layers were combined and washed with brine, then dried over MgSO4, filtered and concentrated to afford an orange oil. The crude oil was purified by flash chromatography on Merck silica gel in 5% EtOAc in hexane. The fractions containing the product were combined and concentrated to afford the title compound as a pale yellow solid (3.090 gm, 63%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (95 mg, 0.43 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (180 mg, 0.47 mmol), 8-hydroxyquinoline (13 mg, 0.086 mmol) and Cs2CO3 (154 mg, 0.47 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (98 mg, 0.52 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The reaction mixture was then heated at 135° C. under nitrogen overnight. The reaction suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, concentrated and purified to afford the title compound (0.12 g, 54%) as a mixture of rotamers: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=8.5 Hz, 0.4H), 7.53 (d, J=8.0 Hz, 0.6H), 7.41 (dd, J=8.0, 6.0 Hz, 2H), 7.33-7.26 (m, 2H), 7.10 (t, J=8.5 Hz 2H), 7.00 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 6.02 (d, J=5.5 Hz, 1H), 5.01 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76 (br s, 1.3H), 3.68 (br s, 0.7H), 3.65 (s, 3H), 2.97 (br s, 2H), 2.05-2.03 (m, 2H), 1.44 (s, 3.1H), 1.37 (s, 5.9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO.ClCCCl.C1CCCCC1.CCOC(C)=O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][NH:16][C:5]2[CH:6]=[C:7]([C:9]3[S:13][C:12]([CH2:14][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:11][CH:10]=3)[N:8]=[C:3]([O:2][CH3:1])[N:4]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3ccc(CN4CCCC4)s3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
A mixture of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [250 mg, 0.68 mmol, Example 8(b)], pyrrolidine (170 μL, 2.03 mmol) and sodium triacetoxyborohydride (502 mg, 2.37 mmol) in MeOH (10 mL) and 1,2-dichloroethane (10 mL) is treated with acetic Acid (116 mL, 2.03 mmol) to bring the pH to 6.0, stirred at ambient temperature for 6 hours, and treated with pyrrolidine (170 μL, 2.03 mmol) and sodium triacetoxyborohydride (502 mg, 2.37 mmol). The reaction mixture is stirred at ambient temperature overnight concentrated by rotary evaporator. The residual gum is partitioned between EtOAc and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to provide a solid, which is subjected to flash column chromatography on silica gel eluting with a mixture of EtOAc and cyclohexane to afford [2-(4-methoxy-phenyl)-ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-pyrimidin-4-yl]-amine [202 mg, 70%, Example 13(a)]. LCMS: RT=5.37 minutes, MS: 425 (M+H). IC50=44 nM
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1ccoc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1C1CCOC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A suspension of 4-methyl-3-(3-furyl) nitrobenzene 1 (470 mg, 2.31 mmol) and 10% Pd/C (245 mg, 0.23 mmol) in methanol (10 mL) was placed under an H2 atmosphere and the resulting reaction was maintained overnight at rt. The reaction mixture was filtered through Celite and the remaining solids were washed with EtOAc. The combined organic portions were concentrated to provide 400 mg (2.26 mmol, 98%) of an amber residue as 2: LCMS m/z 178.2 (MH+), tR=1.53 min.