Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[BH4-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH:10]([OH:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: O=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccccc1C=CC(O)CCc1ccccc1O
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 1,5-bis(2-hydroxyphenyl)penta-1,4-dien-3-one (EF1) (109 mg, 0.41 mmol) in THF/methanol (10/1) (2.5 mL) was added NaBH4 (40 mg, 1.30 mmol) in one portion at 0° C. After stirring for 30 min at this temperature the reaction was quenched with H2O dist and cold brine, diluted with Et2O (10 mL) and neutralized by bubbling CO2 through the dark-red solution (color change to pale yellow). The aqueous phase was extracted with ether, the combined ether layers washed with brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel using 30% EtOAc/hexanes. The product was obtained as a white solid (66%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=C.[CH2:15](O)CO>>[Br:13][C:12]1[C:5]2[O:4][CH:1]([CH3:2])[CH2:15][C:6]=2[C:7]([Cl:14])=[C:8]([C:9]#[N:10])[CH:11]=1
Reactant: C=CCOc1cc(Cl)c(C#N)cc1Br
Reactant: OCCO
Product: CC1Cc2c(Cl)c(C#N)cc(Br)c2O1
Temperature: 25 °C
Yield: 52 %

Procedure:
The compound 38 (2.03 g, 7.45 mmol) in ethylene glycol (5 mL) was subjected to microwave conditions (Biotage®) at 250° C. for 90 min. The reaction mixture was cooled to r.t. and extracted with EtOAc/H2O (50 mL/100 mL). The organic layer was dried over MgSO4, filtered off, and evaporated in vacuo. The residue was purified using normal phase column chromatography to obtain the title product (1.05 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][C:40]4=[O:44])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=6 Hz), 8.53 (1H, s), 8.16 (1H, s), 7.38 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.35 (2H, t, J=6 Hz), 4.13 (2H, s), 3.47 (2H, t, J=7 Hz), 3.18-3.35 (8H, m), 2.19 (2H, t, J=9 Hz), 2.02 (2H, t, J=5 Hz), 1.84-1.94 (2H, m), 1.69-1.76 (2H, m), 1.49-1.62 (4H, m); ES+ MS: 564 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1>Cl.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 53 %

Procedure:
N-[4-(4-methylpiperazine-1-sulfonyl)phenyl]acetamide (2 g, 6.7 mmol) was dissolved in 3 N HCl (50 mL) and 1,4-dioxane (12 mL). The reaction mixture was refluxed for 1 h, evaporated under vacuum, and the rsulting mixture made basic with 30% NH4OH. The desired product was extracted with CH2Cl2, dried (Na2SO4), filtered, and evaporated under reduced pressure to obtain 4-(4-methylpiperazin-1-sulfonyl)aniline as a white solid. MP: 210° C.; Yield 53%; 1H NMR (DMSO d6): δ 2.22 (s, 3H), 2.50 (m, 4H), 2.82 (m, 4H), 6.10 (bs, 2H), 6.62-6.67 (d, 2H, J=10 Hz), 7.32-7.36 (d, 2H, J=8 Hz).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[C:44]([NH:45][S:46]([CH2:49][CH2:50][CH3:51])(=[O:48])=[O:47])=[CH:43][CH:42]=[C:41]([F:52])[C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[N:19](S(C3C=CC=CC=3)(=O)=O)[C:16]2=[N:17][CH:18]=1)=[O:11]>CO>[F:7][C:8]1[C:44]([NH:45][S:46]([CH2:49][CH2:50][CH3:51])(=[O:48])=[O:47])=[CH:43][CH:42]=[C:41]([F:52])[C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[NH:19][C:16]2=[N:17][CH:18]=1)=[O:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(-c2ccc4c(ccn4C)c2)n3S(=O)(=O)c2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccc5c(ccn5C)c4)cc3c2)c1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
2N K2CO3 (1 mL) was added to a solution of 2,6-difluoro-N-(2-(1-methyl-1H-indol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (19 mg, 29 mmol) in MeOH (3 mL), and the mixture was heated to 60° C. for 16 hours. The volatiles were removed under reduced pressure, and the resulting residue was partitioned between EtOAc and water. The layers were separated, and the organic layers were dried (MgSO4), filtered and concentrated. Dichloromethane was added to the residue, and the resulting solid was collected by vacuum filtration giving 2,6-difluoro-N-(2-(1-methyl-1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (10 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.84 (s, 1H), 9.80 (s, 1H), 8.33-8.28 (m, 2H), 8.15 (s, 1H), 7.77-7.73 (m, 1H), 7.57-7.52 (m, 2H), 7.39-7.38 (m, 1H), 7.29-7.25 (m, 1H), 6.86 (s, 1H), 6.50-6.49 (m, 1H), 3.83 (s, 3H), 3.15-3.11 (m, 2H), 1.83-1.73 (m, 2H), 1.03-0.98 (m, 3H); m/z (APCI-neg) M−1=522.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[C:44]([O:45][CH3:46])=[CH:43][C:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:35][CH2:36][C:30]=2[CH:29]=1>>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[N:7][C:2]([NH:27][C:28]2[C:44]([O:45][CH3:46])=[CH:43][C:31]3[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:35][CH2:36][C:30]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2-n2cccn2)n1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3-n3cccn3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-2-pyrazol-1-yl-phenyl)-amine was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product 2-{7-[5-Chloro-4-(4-morpholin-4-yl-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.90 (m, 2H), 8.20 (m, 2H), 7.80 (m, 2H), 7.68 (s, 1H), 7.14 (s, 1H), 7.01 (m, 1H), 6.92 (s, 1H), 6.50 (s, 1H), 4.33 (s, 2H), 3.79 (m, 7H), 3.58 (bm, 2H), 3.35-3.15 (m, 5H), 3.15-3.07 (m, 4H), 2.99 (s, 6H), 2.50 (m, 1H); MS (m/e) 632.51 (M+H).
Reaction SMILES: B.CSC.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:17])([CH3:16])[CH2:13][OH:14]
Reactant: CC(C)(C(=O)O)c1ccccc1F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(CO)c1ccccc1F
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Borane-methyl sulfide (2M in THF, 12.35 mL) was added dropwise to a solution of 2-(2-fluorophenyl)-2-methylpropanoic acid (example 90, step c) (1.5 g) in THF (30 mL). The reaction mixture was stirred at 20° C. for 8 hours. The mixture was quenched by careful addition of methanol until evolution of gas ceased. The solvents were removed under reduced pressure and the residue azeotroped with toluene. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.3 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].CC(C)([O-])C.[K+].C1COCC1.[C:20](=O)([O:23]C)[O:21][CH3:22]>>[CH3:22][O:21][C:20](=[O:23])[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COC(=O)OC
Reactant: Cc1ccncc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Nc1cnccc1C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
The synthesis was carried out by charging 2 grams (1 equiv., 18.5 mmol) 4-Methyl-pyridin-3-ylamine to a solution of 6.55 grams potassium t-butoxide (3 equiv., 55.5 mmol) in 10 ml THF (6.66 euiv., 123 mmol) at 0° C. Upon anion formation, 2.34 ml dimethyl carbonate (1.5 equiv., 27.7 mmol) were charged to the reaction at a rate so that the temperature stayed below 0° C. The reaction was complete within 30 minutes and the red slurry was quenched with 50 ml water (25 volumes) and extracted in 50 ml ethyl acetate (25 volumes). The aqueous layer was extracted with 50 ml ethyl acetate (25 volumes) and then the orange organic layers were concentrated to an orange solid. NMR data showed that t-butanol existed in the product so the solids were slurried in 10 ml toluene (5 volumes) and then concentrated to dryness. This operation was performed three times in order to give very clean light orange solids. (89% yield). 1H NMR: δ8.90 (1 H, brs), 8.28 (1 H, d, J=4.8), 7.16-7.14 (1 H, m), 6.54 (1 H, brs), 3.80 (3 H, s), 2.29 (3 H, s).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41]1>CN(C=O)C>[N:43]1([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH:62][C:3](=[O:4])[CH:2]([F:6])[F:1])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41][O:40][CH2:45][CH2:44]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[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: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)C(F)F
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of 2,2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60° C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].Cl>C1COCC1>[F:10][C:9]1[C:4]([CH:3]=[O:2])=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:6]([N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(OC)c1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Yield: 96.3 %

Procedure:
To a stirred solution of (2-dimethoxymethyl-3-fluoro-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (1.0 g, 2.22 mmol) in THF (10 ml) was added a solution of 4M HCl at room temperature. After 2 hours the THF was removed in vacuo and the residue diluted with water (20 ml) providing a precipitate. The solid precipitate was collected by filtration, washed with water and dried under vacuum to yield the title compound (864 mg, 96%). LCMS (Method B): RT=4.06 min, [M−H]−=403.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:34]1([CH2:39][CH:40]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:49][C:50](O)=[O:51])[CH3:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:34]1([CH2:39][CH:40]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:49][C:50]([N:24]2[CH2:25][CH:26]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:19][CH2:20][S:21](=[O:27])[CH:22]3[CH2:23]2)=[O:51])[CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(CN1CCCC1)Oc1ccccc1CC(=O)O
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(CN1CCCC1)Oc1ccccc1CC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 36.5 %

Procedure:
0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5° C., of 0.69 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.68 g of {[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 25 cm3 of dry dichloromethane, followed by a solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 20 cm3 of dry dichloromethane. After stirring for 2 hours at +5° C. and 20 hours at 20° C., the reaction mixture is washed twice with 50 cm3 of distilled water and dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 32 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate, acetic acid and water mixture (80/20/20 by volume) and collecting fractions of 25 cm3. Fractions 21 to 50 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 8 cm3 of ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl oxide and then dried. 0.45 g of (1RS,4aRS,7aRS)-6-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide is obtained in the form of beige crystals; melting point 126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](c1cc(F)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of (S)-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methyl propane-2-sulfinamide (350 mg, 1.12 mmol) in THF (10 mL) under N2 atmosphere, was dropwise added LHMDS (2.24 mL, 1 M in THF, 2.24 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (240 mg, 1.69 mmol). The mixture was stirred at rt for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×40 mL). The organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (270 mg, yield: 74%); m/z (ES+): 326 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@@H]12

Procedure:
3-Acetoxy-oestra-1,3,5(10)-trien-17β-ol (500 mg., 1.6 mmole) in pyridine (2 ml.) was treated at room temperature for 16 hr. with methanesulphonyl chloride (1 ml.). The solution was diluted slowly with water (25 ml.) then the product was extracted into ether (50 ml.). The extract was washed with 2N-sulphuric acid (25 ml.) then water (50 ml.) and the solvent was evaporated in vacuo. Crystallisation of the residue from slightly aqueous methanol gave the title compound in two crops (total 519 mg., 93%), m.p. 120°-122°.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([CH2:22][CH2:23][CH3:24])=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:11].IC>CC(C)=O>[CH3:1][CH:9]([C:8](=[O:7])[CH2:22][CH2:23][CH3:24])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCCC(O)=CC(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCC(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a stirred suspension of potassium carbonate (596 mg) in acetone (7 mL), was added 3-hydroxy-1-(3-trifluoromethylphenyl)-hex-2-en-1-one (190 mg) followed by iodomethane (0.45 mL). The mixture was heated at reflux for 6 h, cooled to room temperature, and the solvent evaporated at reduced pressure. The resulting oil was dissolved in ethyl acetate (20 mL), washed with water (3×20 mL), dried over sodium sulphate and evaporated at reduced pressure to give the crude product as an oil. Flash silica chromatography afforded 2-methyl-1-(3-trifluoromethylphenyl)-hexane-1,3-dione as an oil (102 mg).
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].[O:30]1[CH2:33][CH:32]([N:34]2[CH2:41][C:38]3([CH2:40][CH2:39]3)[NH:37][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:37]4[CH2:36][CH2:35][N:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:41][C:38]54[CH2:39][CH2:40]5)[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]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CN(C2COC2)CC2(CC2)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC34CC4)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (183 mg, 0.47 mmol), 7-oxetan-3-yl-4,7-diazaspiro[2.5]octane (90 mg, 0.54 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 6 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 5% then MeOH:DCM, 1-5%) followed by recrystallisation from Et2O affording 744 (156 mg, 61%). LCMS (method I): RT 2.53 min [M+H]+ 544.2. 1H NMR (DMSO, 400 MHz): δ 8.00-7.99 (1 H, m), 7.65-7.61 (1 H, m), 7.24-7.23 (2 H, m), 4.53 (2 H, t, J=6.46 Hz), 4.42 (2 H, t, J=6.05 Hz), 4.24 (4 H, brd s), 4.07 (2 H, s), 3.77 (4 H, t, J=4.61 Hz), 3.73 (3 H, s), 3.50-3.42 (1 H, m), 3.26 (2 H, q, J=7.44 Hz), 2.85-2.75 (2 H, m), 2.32 (2 H, t, J=4.72 Hz), 2.17 (2 H, brd s), 1.33 (3 H, t, J=7.44 Hz), 0.72-0.65 (2 H, m), 0.52-0.51 (2 H, m)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[NH:15][C:16](=[O:18])[CH3:17])[NH:11][N:10]=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:5])C.Cl>C(O)C.[OH-].[Na+]>[C:16]([NH:15][C:14]1[CH:13]=[C:12]2[C:8]([C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:10][NH:11]2)=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Temperature: 25 °C
Yield: 105.5 %

Procedure:
A total of 160 mg of 6-acetylamino-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid ethyl ester obtained in Production Example II-7-e was dissolved in 3 ml of ethanol and 1 ml of 5 N aqueous sodium hydroxide solution, and the solution was stirred at 50° C. for 2 hours. After cooling to room temperature, 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 155 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:43].[Na+].C(=O)C>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCN(CC)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Example 290 and sodium triacetoxyborohydride in 9/1 dichloromethane/methanol was added excess acetaldehyde. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by reverse phase preparative HPLC with the AA method to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.35 Hz, 3 H) 1.09 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.55 (m, 2 H) 3.24 (m, 3 H) 3.38 (q, J=6.99 Hz, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 6.87 (d, J=8.82 Hz, 1 H) 7.26 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.88 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=1.84 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 656/658 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][CH2:26][CH2:27]O)[CH2:20]2>>[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[CH:5]3)[CH2:20]2
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Reactant: OCCCN1CC2CC2C1
Product: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2[nH]1)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from (5-hydroxy-1H-indol-2-yl)-morpholin-4-yl-methanone (example 5, step 3) and 3-(3-aza-bicyclo[3.1.0]hex-3-yl)-propan-1-ol (example 5, step 2). The title product was obtained in 49% yield as white solid. MS (m/e): 370.5 (MH+, 100%).