Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:5]([O:4][C:2](=[O:3])[NH:1][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22])[CH3:6]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCOC(N)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)NC(=O)C1c2ccccc2Oc2ccccc21
Reaction time: 17 h
Yield: 66.9 %

Procedure:
To a stirred solution of urethane (0.82 g, 9.21 mmol) and DMAP (0.05 g, 0.41 mmol) in pyridine (10 ml) was added at 0° C. 9H-xanthene-9-carbonyl chloride (1.50 g, 6.13 mmol). Stirring was continued at RT for 17 h, the reaction mixture was evaporated and water (50 ml)/sat. NaHCO3 solution (20 ml) was added. The solid was filtered off and crystallized from water and afterwards from EtOH/hexane to give the product (1.22 g, 67%) as a white solid, m.p. 228° C. (dec.) and MS: m/e=298.2 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]([O:22][CH2:23][CH:24]([OH:27])[CH:25]=[CH2:26])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCCC.CCOC(C)=O.COC(C)(C)C>[C:3]([O:22][CH2:23][CH:24]([O:27][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[CH2:26])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of tetrabutylammonium hydrogen sulfate (367 g, 1.08 mol, 0.1 equiv.) in toluene (4.63 kg) under nitrogen atmosphere was prepared and cooled down to 0° C. 50% aq. NaOH solution (9.09 kg) was slowly added with the temperature kept under 50° C. Crude mixture from Step 4-(2) (3.95 kg of 1-(trityloxy)but-3-en-2-ol in toluene, total weight 6.34 kg) was slowly added with temperature kept under 15° C. The reaction mixture was stirred for 15 min. tert-Butyl bromoacetate (1.01 kg, 5.19 mol, 0.43 equiv.) was added leading to the formation of a slurry. Water (1 kg) was added then tert-butyl bromoacetate (1.55 kg, 7.95 mol, 0.66 equiv) while maintaining temperature below 30° C. The reaction was left to stir overnight. The reaction was followed by TLC (Rf 0.60 in Heptane/EtOAc 20%). Water (9.72 kg) and 2-methoxy-2-methylpropane (10.4 kg) were added then the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg). The organic phase was then concentrated under reduced pressure to generate a crude mixture (4.70 kg). 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (dt, J=7.9, 3.9 Hz, 6H), 7.27-7.19 (m, 6H), 7.14 (dd, J=14.2, 6.9 Hz, 3H), 5.81-5.70 (m, 1H), 5.28 (d, J=17.2 Hz, 1H), 5.21 (d, J=9.9 Hz, 1H), 4.10-3.94 (m, 3H), 3.34 (dt, J=17.7, 8.8 Hz, 1H), 3.18 (dd, J=9.6, 5.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.48, 143.95, 135.69, 128.69, 127.67, 126.86, 118.47, 86.62, 81.07, 80.74, 66.75, 66.41, 28.05.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].S([O-])([O-])(=O)=O.[Mg+2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([NH:1][C:2]1[NH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1c(-c2ccccc2F)[nH]c(NCc2ccccc2)c1C#N

Procedure:
To a solution of 2-amino-3-cyano-4-methyl-5-(2fluorophenyl)pyrrole (Compound No. 1) obtained in Example 5 (0.21 g) in methylene chloride (5 ml) was added a small amount of magnesium sulfate and the mixture was stirred under ice-cooling. Then, a solution of benzaldehyde (0.11 g) in methylene chloride (5 ml) was added dropwise at the same temperature and the mixture was stirred at room temperature for 5 days. The magnesium sulfate was then filtered off and the filtrate was concentrated under reduced pressure. After the residue was dissolved in methanol (15 ml), sodium borohydride (76 mg) was added thereto under ice-cooling. This mixture was stirred at room temperature for 1 hour and the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the ethyl acetate layer was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 50 g; eluent: chloroform/methanol=50/1) and the resulting crystals were recrystallized from benzene/n-hexane to provide the title compound as light-yellow powder (0.17 g). m.p. 151-152° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1.FC1C=CC(OCC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=C(CCN)C=1.Cl.C(N(CC)CC)C.Br[CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>O1CCOCC1.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH2:10][NH:11][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:8]=1
Reactant: NCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 62.5 °C
Reaction time: 12 h

Procedure:
13.8 g (30 mmol) of 2-(5-fluoro-2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethylamine hydrochloride [obtainable by taking up the compound of Example 45A in a 1 M solution of hydrogen chloride in dioxane, reconcentrating the solution and drying the resulting residue] are introduced into 200 ml of DMF, mixed with 32.4 ml (0.23 mol) of triethylamine and heated to 60-65° C. At this temperature, 9.48 g (0.05 mol) of ethyl 5-bromovalerate are added dropwise, and the mixture is stirred for 12 hours. After cooling, the mixture is added to water, adjusted to pH 5 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The resulting residue is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol 10:1). 4.5 g (8.9 mmol, 18% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](=N)[O:12][CH3:13])[CH:6]=[C:7]([Cl:9])[CH:8]=1.C1(C)C=CC=CC=1.[OH2:22]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:12][CH3:13])=[O:22])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: O
Reactant: COC(=N)Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Cl)cc(Cl)c1
Yield: 91 %

Procedure:
To methyl 3,5-dichlorobenzeneethanimidate hydrochloride (1:1) (i.e. the product from Step A1a) (50 g, 0.107 mol) was added to a mixture of toluene (167 mL) and water (167 mL). After 60 min the organic phase was removed, dried (MgSO4), and evaporated to give the title compound as an oil (39 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:42]2[CH:41]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:45]=[CH:44][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: C[C@H](Nc1ncnc(N)c1Br)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4cccc4c(=O)n3-c3ccccc3)c2)cc1
Yield: 59.1 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.35 mmol) was treated with 4-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (205 mg, 0.53 mmol), 2M cesium carbonate (360 μl, 0.72 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol) according to the method described in Example 3 to give 126 mg (59% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1>>[O:9]1[CH2:14][CH2:13][CH:12]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCOCC1
Product: Brc1ccc(OC2CCOCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydropyran-4-ol by the method of Example 10 (b).
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[S:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]1[N:10]([CH2:9][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:11][CH2:12][S:24]1
Reactant: ClCC[NH2+]CC1CCCCCC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CCCCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl -N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6](=[O:17])[N:5]([CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH:3]=1.C(O)C.[CH3:25][NH2:26]>CO>[CH:18]1([N:5]2[C:4](=[O:21])[CH:3]=[C:2]([NH:26][CH3:25])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[C:6]2=[O:17])[CH2:20][CH2:19]1
Reactant: CN
Reactant: O=c1cc(Cl)n(-c2cccc([N+](=O)[O-])c2)c(=O)n1C1CC1
Solvent: CO
Solvent: CCO
Product: CNc1cc(=O)n(C2CC2)c(=O)n1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 55 %

Procedure:
To the mixture (30 g) of 6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and 4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 obtained in Step 3 were added ethanol (300 ml) and a 40% solution (150 ml) of methylamine in methanol, and the mixture was stirred with heating at 80° C. for 4.5 hrs, ice-cooled and the precipitated solid was filtered by suction. The residue was washed with water (1 liter) and dried to give 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 8 (16 g, 55%) as a white solid.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]=[CH2:20])=[O:13])[CH2:11][CH:6]2[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:4]1.C(=O)([O-])O.[Na+].[CH:38](=O)[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C>[ClH:1].[CH2:38]([N:17]([CH2:18][CH:19]=[CH2:20])[CH2:16][CH2:15][NH:14][C:12]([N:10]1[CH2:9][CH2:8][N:7]2[C:3](=[O:2])[O:4][C:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:6]2[CH2:11]1)=[O:13])[CH3:39]
Reactant: CC=O
Reactant: C=CCNCCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: C=CCN(CC)CCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To tetrahydro-3-oxo-1,1-diphenyl-N-[2-[(2-propenyl)amino]ethyl]-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide hydrochloride (0.13 g, 0.29 mmol) was added a 0.5 M aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in a 1,2-dichloroethane solution (5 mL). Acetaldehyde (25 mg, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 8 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added a 4M hydrogen chloride/ethyl acetate solution (1.0 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and then the residue formed powder from 2-propanol-ethyl acetate to obtain the title compound (77 mg, yield 56%).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:29])[C@H:10]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].SC[C@H]([C@@H](CS)O)O.[ClH:38].O1CCOCC1>O1CCOCC1>[ClH:38].[CH2:1]([S:5]([NH:8][C:9](=[O:29])[C@H:10]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O[C@H](CS)[C@H](O)CS
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reaction time: 18 h

Procedure:
To a solution of N-butanesulfonyl-(t-butoxycarbonyl)tryptophanamide (0.71 g, 1.68 mmol) and dithiothreitol (47 mg, 0.3 mmol) in 1,4-dioxane (4 ml) is added 4N HCl/1,4-dioxane (20 ml) at more temperature under nitrogen atmosphere and the mixture is stirred for 18 hours. The reaction mixture is concentrated in vacuo and the solid residue is washed with diethyl ether and dried to give N-butanesulfonyl-tryptophanamide hydrochloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.CN(C)C1C=CC=CC=1.[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.O>O1CCOCC1>[C:24]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:26][C:27]([C:30]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:31])=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 5.53 g (0.03 mol) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 mL of 1,4-dioxane was added 3.64 g (0.03 mol) of N,N-dimethylaniline followed by 6.50 g. of 4-biphenylcarbonyl chloride. The reaction solution was allowed to stand at room temperature for 2 hours and then slowly poured into 2 L of water. On cooling the mixture a crystalline white solid was formed which was collected and dried to provide the title compound (9.5 g). The product was used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@H](C)[C@@H](N)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1R*,3S*,4S*)-3-amino-4-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f68) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH:11]=[CH:12][C:13]([OH:15])=O)=[CH:2]1>C(O)(=O)C>[S:10]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[NH:1][C:2]=2[C:13](=[O:15])[CH:12]=[CH:11]1
Reactant: O=C(O)C=CSc1c[nH]c2ccccc12
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccccc12
Yield: 53.7 %

Procedure:
A solution of 76.7 g (0.35 mole) of 3-(indol-3 ylthio) acrylic acid in 4 liters of 10% polyphosphoric acid in acetic acid is stirred at room temperature for 65 hours. The supernatent is decanted from the sticky precipitate, which is partitioned between chloroform and 5% NaOH solution. The organic phase is washed with water, dried, evaporated and the residue recrystallized from 3 liters of 95% ethanol to give 37.8 g of product, mp 242°-243°C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[OH:30])=[C:23]([O:31][CH3:32])[N:22]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:59]([O:66][CH2:67][CH:68](O)[CH2:69][CH2:70][P:71](=[O:78])([O:75][CH2:76][CH3:77])[O:72][CH2:73][CH3:74])([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60]>O1CCCC1>[C:36]([O:35][C:33]([N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[O:30][CH:68]([CH2:67][O:66][Si:59]([C:62]([CH3:64])([CH3:63])[CH3:65])([CH3:60])[CH3:61])[CH2:69][CH2:70][P:71]([O:72][CH2:73][CH3:74])([O:75][CH2:76][CH3:77])=[O:78])=[C:23]([O:31][CH3:32])[N:22]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Diethyl azodicarboxylate (0.43 ml, 2.75 mmol) was added to a cooled mixture of 2-[bis-(t-butoxycarbonyl)-amino]-9-hydroxy-6-methoxypurine (0.71 g, 1.83 mmol), triphenylphosphine (0.72 g, 2.75 mmol) and diethyl 4-(t-butyldimethylsilyloxy)-3-hydroxybutylphosphonate (0.623 g, 1.83 mmol) in dry tetrahydrofuran (20 ml). The reaction mixture was stirred at ambient temperature for 1 hour, and then evaporated to dryness. The residue was dissolved in diethyl ether, the solution filtered, and the filtrate evaporated to give a yellow oil. This oil was partially purified by column chromatography on silica gel (eluting with dichloromethane:ethanol 97:3) to give 2-[bis-(t-butoxycarbonyl)amino]-9-[1-(t-butyldimethylsilyloxymethyl)-3-(diethoxyphosphoryl)propoxy]-6-methoxypurine as a yellow oil (1.20 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=O)[CH3:20])[C:3]=1[S:22][CH3:23].[CH2:24]([SH:27])[CH2:25][SH:26]>[Fe](Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2([CH3:20])[S:27][CH2:24][CH2:25][S:26]2)[C:3]=1[S:22][CH3:23]
Reactant: CSc1c(C(C)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: SCCS
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CSc1c(C2(C)SCCS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Reaction time: 144 h
Yield: 8.4 %

Procedure:
A mixture of 1 g (2.60 mmol) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-acetyl-4-methylthio-1H-pyrazole, 0.26 ml (3.10 mmol) of 1,2-ethanedithiol, 0.084 g (0.5 mmol) of iron(III) chloride and 25 ml of methylene chloride was stirred at 20° C. under an inert atmosphere for 6 days. The mixture was evaporated and chromatographed so as to give 100 mg of yellow oil of the title compound. Mass spectral analysis gave a molecular weight of 460.
Reaction SMILES: [C:1]([C:5]1[O:14][C:8]2[N:9]=[CH:10][NH:11][C:12](=O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[C:1]([C:5]1[O:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:17])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(=O)[nH]cnc2o1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc2c(Cl)ncnc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A mixture of 6-tert-butylfuro[2,3-d]pyrimidin-4(3H)-one (1.0 g) and POCl3 (10 mL) was stirred at 55-65° C. for 3 h. The reaction mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with aq. NaHCO3 solution, water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluents to give the product as a white color solid (800 mg, 73%), mp 72-74° C. 1H NMR (400 MHz, CDCl3): δ 8.69 (1H, s), 6.48 (1H, s), 1.42 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN1C(=O)CCC1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 5-chloro-2-nitroaniline (100 mg, 0.58 mmol) in NMP (4.5 mL) was treated with morpholine (75 mg, 0.86 mmol) in the presence of triethylamine (0.2 mL, 1.44 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h and upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography afforded the title compound in a 77% yield. 1H NMR: (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=9.6 Hz), 7.29 (bs, 2H), 6.39 (dd, 1H, J=2.8 and 9.6 Hz), 6.22 (d, 1H, J=2.4 Hz), 3.70 (m, 4H), 3.27 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=3)[N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:10]=2)[CH:6]=[N:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[F:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH:8]=3)=[CH:10][N:11]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:15]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCBr)c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
To a solution of 3-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 22; 100 mg; 0.22 mmol) in MeCN (10 mL) was added 1-methylpiperazine (44 mg; 0.44 mmol), K2CO3 (62 mg; 0.45 mmol), and NaI (33 mg; 0.22 mmol). The mixture was stirred at 80° C. for 4 hours, filtered, concentrated, and purified by preparative TLC (DCM/MeOH=10/1) to afford 70 mg (68%) of the title compound as a yellow solid.