Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (4.5 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and methyl chloroformate (4.5 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.20 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][OH:14])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cn(CCO)c2ncc(Br)cc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCOS(C)(=O)=O)c2ncc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of ethyl 6-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 17, 800 mg, 2.34 mmol) and triethylamine (473 mg, 4.69 mmol) in dichloromethane (50 mL) was cooled to 0° C. and methane sulphonyl chloride (400 mg, 3.50 mmol) was added drop wise. The mixture was allowed to stir at room temperature for 3 h. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 700 mg, (71%) of ethyl 6-bromo-1-{2-[(methylsulfonyl)oxy]ethyl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, which was taken without further purification to next step.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[BH4-].[Na+].[C:33](O)(=O)[CH3:34]>>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH2:33][CH3:34])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg), in glacial acetic acid (0.05 mL) was added sodium borohydride (2 mg) in two portions. After addition, the mixture was stirred at room temperature for overnight. The mixture was concentrated under vacuum. Then saturated sodium bicarbonate and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear colorless sticky oil (1.8 mg, 56% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]([SiH2:26][O:27][C:28]([CH3:35])([CH3:34])[C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([CH3:25])([CH3:24])[CH3:23].CN1CCN(C)C1=O>C(OCC)(=O)C>[C:22]([SiH2:26][O:27][C:28]([CH3:35])([CH3:34])[C:29]1[N:30]=[CH:31][N:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:33]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c[nH]cn1
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Temperature: 140 °C
Yield: 33.1 %

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 333 mg (1.57 mmol) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-1H-imidazole and 1 ml of dry 1,3-dimethyl-2-imidazolidinone is heated to 140° C. (oil bath temperature) in a closed vial for 4 hours. After cooling, the orange solution is diluted with ethyl acetate and the organic phase washed with water and brine and dried over Na2SO4. Evaporation of the solvent gives an oil which is purified by medium pressure chromatography on silica gel with ethyl acetate/acetic acid 98:2 as eluent, yielding 53 mg of N-{6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide, m.p. >270° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>CN(C=O)C.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[CH:20]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1Br
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(OC)cnnc1-c1cccc(C(F)(F)F)c1
Yield: 41.6 %

Procedure:
4-Bromo-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (1.0 g, 0.003 mole, Compound No. 57), vinyltributyltin (1.1 g, 0.0034 mole) and trans-benzyl(chloro)bis-(triphenylphosphine)-palladium(II) (20 mg) were heated to 110° C. in DMF (50 mL) under N2 for 4 h. The reaction was then cooled and partitioned between aqueous KF and ethyl acetate. The KF solution was extracted with additional ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered through silica gel and then evaporated in vacuo. The crude oil was then chromatographed on a Prep-500 to give 4-ethenyl-5-methoxy-3-[3-(trifluoromethyl) phenyl]pyridazine (0.35 g, 42% yield, Compound No. 55) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH:26]1CC[CH2:29][CH2:28][CH2:27]1>CN(C=O)C.O>[CH2:24]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)[C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: BrCCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a stirred solution of tert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate (3.79 g, 16.9 mmol) in DMF, cooled to 0° C. with a brine/ice bath, was added potassium tert-butoxide (126 mg, 1.07 mmol). The mixture was stirred 5 minutes at 0° C. then 1-bromo-2cyclohexylethane (205 mg, 1.07 mmol) was added. After stirring at room temperature for 4 h, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL). The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded tert-butyl hexyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as a yellow oil [3.60 g, yield 69%; HPLC/MS: m/z=309 (M+H); log P(HCOOH)=3.94].
Reaction SMILES: [N:1]([C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37])=[N+]=[N-].C(O)(=O)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N)c(F)cc2c1=O
Yield: 68.1 %

Procedure:
Ethyl 7-azido-8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (650 mg) was dissolved in methanol (20 ml). An acetic acid suspension (3 ml) of 20% palladium hydroxide (100 mg) was added to this solution, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After palladium hydroxide was removed by filtration, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (423 mg) as a liver-colored amorphous substance.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=O)=[CH:14][C:13]=1[N+:30]([O-:32])=[O:31]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[CH2:1])=[CH:14][C:13]=1[N+:30]([O-:32])=[O:31]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a mixture of methyltriphenylphosphonium bromide (15.6 g, 44 mmol) in tetrahydrofuran (100 mL) at 0° C. was added a solution of sodium hexamethyldisilazide (22 mL, 2.0M solution in THF, 44 mmol), and the resulting mixture was stirred for one hour at 0° C. Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (7.0 g, 22 mmol) in tetrahydrofuran (50 mL) was then added drop wise to the yellow reaction mixture and stirred at 0° C. for 30 minutes and at room temperature for four hours. The brown reaction mixture was diluted with hexanes, filtered through silica gel, and the filtrate was washed with water (100 mL), brine solution (100 mL), dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography (silica gel, eluting with 5-10% ethyl acetate-hexane) to give methyl 2-[1-(4-chloro-3-nitrophenyl)ethenyl]benzoate (0.95 g, 3 mmol, 14% yield). 1H NMR (400 MHz, CDCl3): 7.95-7.93 (dd, 1H), 7.73-7.72 (d, 1H), 7.61-7.57 (dt, 1H), 7.50-7.46 (dt, 1H), 7.46-7.43 (d, 1H), 7.39-7.34 (m, 2H), 5.77 (s, 1H), 5.37 (s, 1H), 3.63 (s, 3H); MS (EI) for C16H12ClNO4: 318 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)CON(C(C)(C)c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CON(C(C)(C)c2ccc(C(=O)CCCCl)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 ML THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[N:17]([C:18]([NH2:20])=[O:19])[N:16]=[C:15]([CH3:21])[C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH3:30].C(OC)(OC)(OC)C.O>C(#N)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:14]2[C:15]([CH3:21])=[N:16][N:17]3[C:18]([OH:19])=[N:20][C:1]([CH3:2])=[N:12][C:13]=23)=[C:23]([CH3:30])[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(-c2c(C)nn(C(N)=O)c2N)c(C)c1
Agent: COC(C)(OC)OC
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2c(C)nn3c(O)nc(C)nc23)c(C)c1
Temperature: 87.5 °C
Reaction time: 0.75 h

Procedure:
p-Toluenesulfonic acid (29.2 g, 154 mmol) in acetonitrile (100 mL) was added to the reaction mixture described in Example 3 containing 5-amino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole-1-carboxylic acid amide. The resulting mixture was heated to 85-90° C. and trimethyl orthoacetate (160 mL, 1.26 mol) was added over 5 minutes during the heating. The reaction was held for about 45 minutes in the desired range with a total of 1.5 hours of heating time from the initiation of the heating cycle. Reaction progress was monitored by HPLC. Water (1.50 L) was added over 5 minutes with a temperature drop to about 60° C. The resulting mixture was cooled to about 20° C. over 1 hour and the product isolated by filtration. The yield was 136 g (78.0% with a purity of 99.5 A %).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:16][NH:17][CH3:18])=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[OH:34][CH2:35][C@@H:36]1[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]2[CH:45]=[C:46]([C:49](O)=[O:50])[CH:47]=[CH:48][C:38]=2[NH:37]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[CH3:18][N:17]([CH2:16][C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:20][CH:19]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:49]([C:46]1[CH:47]=[CH:48][C:38]2[NH:37][C@H:36]([CH2:35][OH:34])[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]=2[CH:45]=1)=[O:50]
Reactant: CNCc1cc2ccccc2n1Cc1ccc(O)cc1
Reactant: CN1Cc2cc(C(=O)O)ccc2N[C@H](CO)C1=O
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: CN(Cc1cc2ccccc2n1Cc1ccc(O)cc1)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 92.2 %

Procedure:
According to the procedure of Example 1 (a), except substituting 1-(4-hydroxybenzyl)-2-(methylaminomethyl)indole (0.40 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2-(hydroxymethyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.34 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.63 g, 92%) was prepared as an off-white solid: MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.2 g, 3.07 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (640 mg, 3.37 mmol) and 4 Å powdered molecular sieves (2.5 g) in DCE (65 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (1.3 g, 6.13 mmol). The reaction mixture was stirred for 18 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%). A mixture of the resulting yellow powder and 3-mercaptopropyl ethyl sulphide silica (250 mg) was stirred in a mixture of EtOH and DCM at 50° C. for 3 h. The mixture was filtered and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with EtOH and the product eluted with 2M NH3/EtOH. The resulting oil was triturated with Et2O and dried in vacuo at 60° C. affording 354 as a pale yellow solid (1.26 g, 73%). LCMS (Method I): RT 2.43 min [M+H]+ 566.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.22 (m, 2 H); 4.34 (m, 4 H); 3.89-3.80 (m, 9 H); 3.59 (m, 2 H); 3.39-3.23 (m, 3 H); 3.12-3.04 (m, 6 H); 2.85 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](O)=[O:39]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[CH:30]=[CH:31][C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:28]=4[O:27][CH3:26])=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1c(C(=O)O)ccc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5c4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-methoxynaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([CH:14]=O)=[C:9]([Cl:16])[N:8]=1.Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:19]>C(N(CC)CC)C>[Cl:16][C:9]1[N:8]=[C:7]([Cl:6])[N:12]=[C:11]2[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=[CH:14][C:10]=12
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
155 ml of THF are added with stirring to a mixture of 5.17 g of 2,4,6-tri-chloropyrimidine-5-carbaldehyde and 5.85 g of ethyl hydrazinoacetate hydrochloride. The mixture is cooled to 10° C., and 6.78 ml of triethylamine are added dropwise. The mixture is stirred at RT for a further 1 h. The deposited precipitate is separated off (not the product). The filtrate, which contains the product, is subjected to conventional work-up, giving 3 g of ethyl (4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)acetate (“12”).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([C:39]1[CH:43]=[C:42]([C:44]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]3[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]2=[O:25])=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cc(C(C)(C)C)nn3C)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (40 mg, 0.08 mmol) in DMF (2 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (18 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol). The reaction was stirred at RT for 14 h, partially concentrated, and purified by RP-HPLC to affor 20 mg of the title compound. MS found: (M+H)+=538.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([N:13]=[C:14]=[S:15])=[O:12])=[CH:9][CH:8]=1)#[N:6]>C1(C)C=CC=CC=1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]([NH:4][CH:1]([CH3:3])[CH3:2])=[S:15])=[O:12])=[CH:16][CH:17]=1)#[N:6]
Reactant: N#Cc1ccc(C(=O)N=C=S)cc1
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)NC(=S)NC(=O)c1ccc(C#N)cc1

Procedure:
Isopropylamine (5.6 ml) was added dropwise to a mixture of 4-cyanobenzoyl isothiocyanate (11 g) and toluene (100 ml) at 60° C., and the insoluble substance in the reaction solution was filtered off. After allowing to stand for cooling, the precipitated crystals were recrystallized from toluene to give 1-(4-cyanobenzoyl)-3-isopropylthiourea (12.35 g) as pale yellow prisms.