Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:15])=[N:12][C:13]=1[CH3:14]>C(#N)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:15]=2)[C:13]=1[CH3:14]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=CC(Br)C=O
Solvent: CC#N
Product: Cc1c(Br)ccc2ncc(C=O)n12
Yield: 28 %

Procedure:
Bromomalonaldehyde (464 mg, 3.07 mmol) was added to a solution of 5-bromo-6-methylpyridin-2-amine (500 mg, 2.67 mmol) in acetonitrile. The reaction mixture was refluxed for 1 hour. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 0.5% methanol in chloroform gradient to obtain the title compound. Yield: 28%; 1H NMR (DMSO-d6; 300 MHz): δ 10.06 (s, 1H), 8.51 (s, 1H), 7.86-7.83 (d, 1H, J=9.3 Hz), 7.68 (d, 1H, J=9.3 Hz), 3.03 (s, 3H); MS: m/z 240.1 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)(=[O:33])[CH3:32]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Product: CC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[C@H:34]([CH3:33])[CH2:38][O:37][C:36]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2N2CCCS2(=O)=O)CC1
Yield: 84.4 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (455 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2(CNC(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 49.3 %

Procedure:
A solution of 3,4-Dichlorobenzoylchloride (1.05 g.,) in benzene (10 ml) was added dropwise over 40 mins. to a stirred solution of 1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (1.06 g.,) in benzene (15 ml). The mixture was heated under reflux for 1 hr. on a steambath and the solution was evaporated. The solid residue was dissolved in ethanol, acidified with ethereal HCl and evaporated to give a white solid. This solid was suspended in water made alkaline with 5NNaOH and extracted with chloroform (x2). The combined chloroform extracts were dried (anhyd.Na 2 SO4) and evaporated. The solid residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and crystallised from petroleum ether (80°-100° ) to give 1-[1-(3,4 Dichlorobenzamido methyl) cyclohexyl] -4-methyl piperazine (0.95 g; 49%) m.p. 143° -146°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH2:30][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCCNCC1
Agent: Cl
Product: CS(=O)(=O)N1CCCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH:6]1)=[O:4].[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:9]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[NH:6][CH:5]2[C:3]([OH:4])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1NC(CC(C)(C)Cc2ccc(OC)cc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 126b (4 g, 6.8 mmol) in tetrahydrofuran (60 mL) was added an aqueous solution (1 N) of NaOH (20 mL, 20 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 3 h. The “pH” of the mixture was adjusted to ˜4-5 by aqueous HCl solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid as a light yellow solid (4 g, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a light yellow solid (9.6%). LCMS: m/z=525.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.41 (s, 1H), 7.34 (d, 1H, J=7.1 Hz), 7.18 (m, 6H), 4.50 (m, 1H), 2.84 (m, 3H), 2.23 (m, 1H), 2.07 (m, 2H), 1.76 (m, 1H), 1.31 (s, 3H), 1.26 (d, 3H, J=6.6 Hz), 1.18 (s, 3H), 0.86 (d, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccccc21
Solvent: CC(=O)O
Product: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccc([N+](=O)[O-])cc21

Procedure:
1.6 gm (4.5 millimols) of 2-carboxy-4-oxo-6,6-dimethyl-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran (see Example 6) were stirred for 24 hours in a mixture of 35 ml of acetic acid and 5 ml of fuming nitric acid. The yellow precipitate formed thereby was filtered off and recrystallized from methanol/acetone. 1.5 gm (83.3% of theory) of the compound named in the heading, m.p. 278°-279° C, were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([Cl:13])=[C:8]([CH3:14])[C:3]=1/[C:4](=[N:6]/[OH:7])/[NH2:5].[OH:15][C:16]1[C:24]([O:25][CH3:26])=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:4]2[N:5]=[C:20]([C:19]3[CH:23]=[C:24]([O:25][CH3:26])[C:16]([OH:15])=[C:17]([N+:27]([O-:29])=[O:28])[CH:18]=3)[O:7][N:6]=2)=[C:8]([CH3:14])[C:9]([Cl:13])=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a second vessel, (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (201.2 g, 1.24 eq) is suspended in 1,4-dioxane (720 mL, 4.5 vol) and the suspension is cooled to 10° C. The residue of example 3e in 1,4-dioxane is added slowly maintaining the temperature below 20° C. A clear orange solution is formed. After complete addition, the reaction mixture is stirred at 20° C. for 1 hour. Pyridine (483.7 mL, 8 eq) is then charged and the reaction mixture is heated slowly to 115° C. The mixture is stirred at 115° C. for 6 hours. The solution is then cooled to 20° C. Dioxane/pyridine is distilled off.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH3:20])=[CH:16]2)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCCCCC>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH3:20])=[CH:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc2ccc(OC)cc2c1
Yield: 90 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and 1-octyne (13.78 g, 0.125 mol), 7-octyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-octyn-1-yl-2-methoxynaphthalene (22.9 g, yield of 86%). The obtained 7-octyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (213 ml) under a hydrogen atmosphere by adding 10% Pd/C (2.13 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-octyl-2-methoxynaphthalene (compound (3)-10, 24.30 g, yield of 90%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[F:9][C:10]1[CH:11]=[C:12]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(F)c2)c1Br
Yield: 88 %

Procedure:
3-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-fluorobenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 125°-128° C., yield 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[O:36][N:35]=[C:34]([OH:37])[CH:33]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]5[O:36][N:35]=[C:34]([OH:37])[CH:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: Oc1cc(CCl)on1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cc(O)no1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3-hydroxyisoxazol-5-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 5-chloromethyl-3-hydroxyisoxazole following General Procedure H.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1([F:36])[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:21]=3)=[CH:16][C:14]=2[NH2:15])[CH2:8]1>N1C=CC=CC=1>[F:36][C:7]1([F:6])[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:33])([F:34])[F:35])[N:21]=3)=[CH:16][C:14]=2[NH:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Methanesulfonylchloride (29.23 mg; 0.26 mmol; 0.6 eq.) was added to a solution of Example 41 (75 mg; 0.43 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 36 hours then concentrated in vacuo. The residue was purified by column chromatography (c-hexane/ethyl acetate, 70/30) followed by crystallization from ethyl acetate/n-pentane to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C#N)cc1F
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-fluoro-4-methoxybenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 80-85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more hexane/ether (2/1). The pale yellow solid 3-fluoro-4-methoxy-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide (3.95 g, 74%) was used in the next reaction without further purification: mp (DSC) 195C. Anal. Calc'd. for C15H15N2SO3F: C, 55.89, H, 4.69, N, 8.69. Found: C, 55.92, H, 4.74, N, 8.53.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)=[O:17])=[CH:11][C:10]=1[C@:26]12[CH2:34][O:33][C@H:32]([CH3:35])[C@H:31]1[C:30](=[O:36])[N:29]([CH3:37])[C:28]([NH:38]C(=O)OC(C)(C)C)=[N:27]2>C(Cl)Cl>[NH2:38][C:28]1[N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]2[C@@H:32]([CH3:35])[O:33][CH2:34][C@:26]2([C:10]2[CH:11]=[C:12]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:17])[CH:13]=[CH:14][C:9]=2[F:8])[N:27]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(NC(=O)OC(C)(C)C)=N4)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a stirred solution of tert-butyl ((4aS,5R,7aS)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (210 mg, 0.40 mmol) in DCM (2 mL) at RT. The mixture was stirred at RT for 1 h. The reaction mixture was evaporated and the residue was loaded on to a SCX cartridge (5 g). The cartridge was eluted with methanol (2×20 mL) and then 2M NH3 in MeOH (1×20 mL). The ammonia-methanol fraction was evaporated. The residue was treated with Et2O/hexanes and the resulting solid was collected by filtration and dried in vacuo to give the title compound (105 mg, colourless solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.06 Hz, 3H) 2.99 (d, J=8.84 Hz, 1H) 3.10 (s, 3H) 4.02 (s, 3H) 4.05-4.14 (m, 1H) 4.14-4.22 (m, 2H) 6.04 (br. s., 2H) 7.16 (dd, J=10.99, 9.22 Hz, 1H) 7.70-7.83 (m, 2H) 8.41 (d, J=1.26 Hz, 1H) 8.88 (d, J=1.26 Hz, 1H) 10.58 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.O>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=1)([O-:3])=[O:2]
Reactant: O=C1CCCCC1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
The mixture of p-nitrophenylhydrazine (12) (15.0 g, 97.9 mmol) and cyclohexanone (10.15 ml, 97.9 mmol) in acetic acid (45 ml) was heated and stirred for 20 minutes at 60° C. To the reaction mixture was added conc. hydrochloric acid (15 ml) and the resulting mixture was heated for 1.5 h at reflux. To the reaction mixture was added water (50 ml), heated for 10 minutes at reflux, and allowed to cool to room temperature. The precipitated crystal was filtered off, washed with water, and recrystallized from ethanol-water to give 6-nitrotetrahydrocarbazole (13) (17.0 g; yield 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.O[CH:29]([C:35]1C2C(C3C=CC=CC=3C=1O)=CC=CC=2)[C:30](OCC)=O>>[O:26]=[C:20]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[O:12][S:13]([C:16]([F:17])([F:19])[F:18])(=[O:15])=[O:14])=[CH:35][CH:29]=[CH:30][CH:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(O)c1c(O)c2ccccc2c2ccccc12
Reactant: CCOC(=O)C(=O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)C(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate in Example 20, using ethyl 2-hydroxy-2-(10-hydroxyphenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: 400 MHz, (CDCl3) δ: 8.77-8.74 (m, 2H), 8.25 (d, J=4.0 Hz, 1H), 7.87-7.84 (m, 2H), 7.81-7.77 (m, 2H), 7.70-7.67 (m, 2H), 4.44-4.38 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). 17F-NMR: 400 MHz, (CDCl3) δ: −73.18 (s).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH2:37][CH2:38][O:39][CH3:40])=[C:35]=[S:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH2:37][CH2:38][O:39][CH3:40])=[S:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COCCN=C=S
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(=S)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 2.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol), obtained in Example B19, and 1-isothiocyanato-2-methoxy-ethane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The pure fractions were collected and the solvent was evaporated, yielding 0.003 g (2.4%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(2-methoxyethyl)-thiourea, MS(ESI) m/z: 593 595 597.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:37])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc(C)sc2-c2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Following the procedure described in Example 1 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-thiazol-4-yl)aniline and ethyl isocyanate provided the title product. ESMS [M+H]+: 532.2