Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][CH2:37][OH:38])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: C1COC1
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(/C(=C(/CCCO)c2ccccc2)c2ccccc2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Clomiphene (3.8 g, 9.3 mmol) was dissolved in tetrahydrofuran (50 ml), cooled to -40° C. and then treated with t-butyl lithium (1M in pentane, 20 mmol). After 10 minutes, trimethylene oxide (6 ml, 93 mmol) was added, the mixture stirred for 16 hours at room temperature, and then poured into water. The product was extracted with ether and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield purified trans-product (1 g, 25%), m.p. 93°-95° C. and cis- product (N,N-diethylhydroxymethyl tamoxifen) (1.0 g, 25%), m.p. 85°-87° C. Anal. (C29H35NO2)C,H,N. Calc., C:81.08, H:8.21, N:3.26; Found, C:80.56, H:7.94, N:3.32. Values for aliphatic protons are presented in Table 3.
Reaction SMILES: [CH2:1]1[C@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[BH4-].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)C>[OH:21][C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C@:19]1([CH3:20])[C:6](=[CH:5][C:4](=[O:22])[C@@H:3]2[CH2:1][C@@H:2]21)[CH2:7][CH2:8]3
Reactant: C[C@@]12C(=CC(=O)[C@@H]3C[C@@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
3.2 g. of 1α,2α-methylene-4-androstene-3,17-dione is dissolved in 50 ml. of absolute ethanol, cooled to 0° C., and mixed with 0.5 g. of sodium borohydride in incremental portions. After a reaction period of 3 hours with ice cooling. The mixture is stirred into 50 ml. of semisaturated sodium dihydrogen phosphate solution. The thus-precipitated product is filtered off and washed with water. After recrystallization from ethanol, 1.95 g. of 17β-hydroxy-1α,2α-methylene-4-androsten-3-one is obtained and gives after acetylation with acetic anhydridepyridine at room temperature, strongly anabolic 17β-acetoxy-1α,2α-methylene-4,6-androsten-3-one, "Arzneim. Forschung" (Drug Research) 15 (1965) : 1168.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([S:36]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])(=[O:38])=[O:37])[CH2:33][O:34][CH3:35])[C:27]=2[F:47])[CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:49](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:49])[CH2:22][CH2:21]3)=[N:17][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([S:36]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])(=[O:37])=[O:38])[CH2:33][O:34][CH3:35])[C:27]=2[F:47])[CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: COCN(c1cccc(-c2nc(C3CCNCC3)sc2-c2ccnc(CNC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCN(c1cccc(-c2nc(C3CCN(C)CC3)sc2-c2ccnc(CNC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}methylcarbamate (65 mg, 0.09 mmol) was dissolved in MeOH (5 mL) and glacial acetic acid (15 μL, 0.26 mmol). 37% aqueous formaldehyde (6.5 μL, 0.13 mmol) and sodium cyanoborohydride (8.5 mg, 0.17 mmol) were then added to the mixture, that was stirred at r.t. for 1 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 15% aqueous ammonia. The organic phase was dried over Na2SO4 and evaporated to dryness, to give 34 mg of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}methylcarbamate that were employed for the next step without any further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([OH:24])=[O:23]>>[C:22]([C:25]1[CH:30]=[C:29]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH:28]=[CH:27][CH:26]=1)([OH:24])=[O:23]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc(C(=O)O)c3)nc2c1
Yield: 83.8 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) and 3-carboxyphenylboronic acid (145.6 mg, 0.88 mmol, 2.00 equiv) as reactants. Purification via silica gel column (DCM/MeOH (20:1)) yielded 141.8 mg (78%) of methyl 3-(3-carboxyphenyl)-2-phenylquinoxaline-6-carboxylate as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[NH:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][NH:27][CH2:26]1)(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CCCCO>[ClH:52].[NH2:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][N:27]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:26]1
Reactant: ClCCl
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](C4CC4)[C@H](N)C3)c12
Product: Cl
Temperature: 146 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g, 0.67 mmol; Example 15, Step A), tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate (0.48 g, 2.00 mmol; Example K) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (2 mL) was stirred at 146° C. (bath) for 20 hours. The solvent was removed. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-80% CH3CN/water, 25 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.17 g, 52%) as a solid. 1H NMR (400 MHz, D2O) δ 8.21 (s, 1H), 7.26 (s, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.11 (m, 2H), 2.60 (m, 1H), 1.88 (m, 1H), 1.82 (m, 1H), 1.52 (m, 1H), 1.16 (m, 1H), 1.07 (t, 6H), 0.77 (m, 1H), 0.39 (m, 1H), 0.14 (m, 1H), 0.11 (m, 1H). LCMS (APCI+) m/z 420 (M+H)+.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:12](Cl)(Cl)=[O:13].C(Cl)([Cl:18])=O.C1C=CC=CC=1.Br>C1C=CC=CC=1>[Br:2][CH2:3][C:4]1[CH:10]=[C:9]([Cl:18])[CH:8]=[CH:7][C:5]=1[N:6]=[C:12]=[O:13]
Reactant: Nc1cccc(Cl)c1CBr
Reactant: O=C(Cl)Cl
Agent: Br
Solvent: c1ccccc1
Product: O=C=Nc1ccc(Cl)cc1CBr

Procedure:
2.3 g of 2-bromomethyl-3-chloroaniline hydrobromide are added to 30 ml. of 12% phosgene in benzene. The mixture is heated to reflux in a 250 ml. flask fitted with a Dean-Stark trap and condenser. Small amounts of phosgene/benzene are carefully added until the hydrobromide is no longer detected (as indicated by following the reaction on thin layer chromatographic plates). The benzene solvent is removed from the reaction mixture by evaporation, then the 2-bromomethyl-4-chloroisocyanate product is recovered by vacuum distillation (at about 50° to 56° at about 0.05 to 0.03 mm Hg).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NCCN(C)C)cc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A solution of ethyl 4-fluorobenzoate (20 g), N,N-dimethylethylenediamine (20 g) and potassium carbonate (32.9 g) in dimethylsulfoxide (200 mL) is stirred at 80° C. for 3 days. After cooling to room temperature, to the reaction mixture is added ethyl acetate and water, and the mixture is stirred and extracted with ethyl acetate (×2). The organic layer is treated with 10% HCl to transfer basic materials to the aqueous layer. The aqueous layer is washed with ethyl acetate, neutralized with 10% sodium hydroxide solution and extracted with ethyl acetate (×3). The combined extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=8:1→4:1) to give ethyl 4-[[2-(dimethylamino)ethyl]amino]-benzoate (12.45 g, yield; 44%) as an oil. MS (APCI) m/z: 237 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:37]1([CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:38][CH2:39]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 664.5 [(M+H)+]
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([CH:25]=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([C:25]([OH:11])=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C=O)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
An aqueous solution (1 ml) of sodium dihydrogenphosphate (24 mg, 0.20 mmol), an aqueous solution (3.5 ml) of sodium chlorite (123 mg, 80%, 1.09 mmol) and aqueous hydrogen peroxide (0.08 ml, 30%) were added to an acetonitrile solution (2.5 ml) of 6-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (112 mg, 0.26 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (106 mg, 0.23 mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OCC4C=CC=CC=4)=O)=[CH:13][CH:12]=3)[C:3]=12>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(NC(=O)OCc4ccccc4)cc3)c3c(N)ncnc32)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)CC1
Reaction time: 96 h
Yield: 66.3 %

Procedure:
To a solution of tert-butyl 4-[4-amino-3-(4-[(benzyloxy)carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (5.0 g, 0.0092 mol) in terahydrofuran (150 mL) 10% palladium on carbon (1.0 g) was added and the reaction mixture was hydrogenated on a Parr shaker over 96 hours. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was triturated in n-heptane and the precipitate was collected by filtration and dried to yield tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (2.51 g, 0.0061 mol) as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[CH:33]=[CH2:34]>>[CH2:34]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: C=CCN1Cc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc2C1=O
Yield: 93 %

Procedure:
In the same manner as in Example 51, the title compound (51 mg) was prepared from the compound (50 mg) obtained in Example 50 and allyl bromide (22 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:31])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17](C(C)C)[CH2:16][C:15]=2[C:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:13]1.Cl>C(O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:31])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:13]1
Reactant: CC(C)N1CCc2c(c(-c3ccc(F)cc3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Agent: Cl
Solvent: CCO
Product: O[C@@H]1Cc2c(F)cc(F)cc2[C@H]1n1nc(-c2ccc(F)cc2)c2c1CCNC2
Temperature: 80 °C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
According to Scheme 8: A mixture of (1R,2R)-4,6-difluoro-1-[3-(4-fluoro-phenyl)-5-isopropyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-indan-2-ol (11ae) (0.2 g, 0.468 mmol), ethanol (14 ml) and 2N aqueous HCl (14 ml) was stirred at 80° C. for 6h. The mixture was concentrated in vacuo. After addition of aqueous saturated NaHCO3, the mixture was extracted 3 times with ethyl acetate, solvents were evaporated in vacuo and the residue freeze-dried from CH3CN-water to give 0.170 g of (1R,2R)-4,6-difluoro-1-[3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-indan-2-ol (13a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[O:9][CH2:8]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH:14]=2)[O:9][CH2:8]1
Reactant: ClCc1ccccn1
Reactant: COc1cccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)c1
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2COc3ccc(OCc4ccccn4)cc3[C@@H]2O)c1

Procedure:
By the method of Example 13, using flash chromatography with 40:9:1 CH2Cl2 :hexane:isopropanol as eluant and recrystallization from 1:1 toluene:hexane, the title product of Example 25 (0.37 g, 0.00128 mol) and 2-picolyl chloride were converted to present title product, 0.15 g (30%), m.p. 105-107° C. MS (m/e) calculated: 379.1424, found: 379.1394.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:24].[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:24][C:23]1[C:6]2[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:25]=[O:26]
Reactant: O=C(Cl)Cl
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N=C=O)c2Cl
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g (0.01 mol) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 60 ml of 1,2-dichloroethane is added dropwise while stirring to a solution of 1.5 g (0.015 mol) of phosgene in ice-cooled 1,2-dichloroethane so that the reaction temperature does not exceed 10°. Subsequently, the reaction mixture is heated at reflux while stirring for a further 10 minutes, whereupon it is cooled to ca 10° and made basic with triethylamine. There is thus obtained a solution of [6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate which can be stored in the cold for several hours with the exclusion of moisture. It is further processed without isolation of the isocyanate contained therein.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>CN(C=O)C.CN(C)C=O>[CH3:2][CH2:3][O:4][CH2:5][CH3:1].[CH2:7]([O:6][CH2:10][CH3:9])[CH3:8]
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: CCOCC

Procedure:
THF—tetrahydrofuran, DMF—N,N-dimethylformamide;
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)(=O)=O.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:8]12([CH2:7][O:6][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:25][CH:26]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: O=S(=O)(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of Intermediate 34 (4.2 g, 14.07 mmol) in anhydrous dimethylformamide (12 mL) and a solution of Intermediate 20 (0.98 g, 4.14 mmol) in anhydrous dimethylformamide (2 mL) was added cesium carbonate (1.8 g, 5.62 mmol). The reaction mixture was stirred at 65° C. for 72 hours. The crude was poured into water and extracted with ether. The organic layer was washed with a solution of sodium hydroxide 2N, water and brine. The solvent was removed under reduced pressure and the title compound was obtained as an oil (1.3 g, 67%) and used in the next step without further purification. MS (M+): 386.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C@@H:8]1([N:17]2[CH:24]=[C:23]([I:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@@H:9]1[OH:10]>N1C=CC=CC=1>[I:25][C:23]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[N:17]([C@@H:8]2[O:14][C@H:13]([CH2:15][O:16][C:5](=[O:7])[CH3:6])[C@@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@@H:9]2[O:10][C:9](=[O:10])[CH3:8])[CH:24]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)cc1I
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 187.5 %

Procedure:
Acetic anhydride (1.04 ml, 11 mmol) was added to a solution of 1 g of 1-(β-D-arabinofuranosyl)-5-iodouracil from Example 4(c)(2.7 mmol) in 10 ml of dry pyridine. After stirring for 3 hours at room temperature, the solvent was evaporated and the residue was co-evaporated with CH2Cl2 several times. The residue was triturated with ethanol, the solid filtered and dried to give 1.256 g (93%) of the title compound, melting at 175°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[C:26]([CH3:27])[CH:25]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: Cc1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (360 mg) in DMF (5 mL) was added potassium carbonate powder (555 mg) and 3-methylbenzyl bromide (774 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:14])[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH2:8].[P:15]([O-:20])([O:18][CH3:19])[O:16][CH3:17]>>[CH3:17][O:16][P:15]([CH2:8][CH:7]([C:6]([O:5][CH3:4])=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:20])[O:18][CH3:19]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COP([O-])OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(CP(=O)(OC)OC)C(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
8 ml of a 30% sodium methylate solution are added dropwise to 158 g (1 mol) of itaconic acid dimethyl ester and 110 g of dimethyl phosphite at 60° C. The exothermic reaction is by that time completed. The mixture is then stirred for one hour at 100° C. and concentrated by evaporation. Quantitative yield of a colorless liquid.