Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:6]1=[O:32])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[C:6]1=[O:32]
Reactant: COc1ccc([C@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc([C@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2O)cc1
Yield: 66.1 %

Procedure:
To a solution of 1.5 g (0.0033 mol) of cis-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2-(dimethylamino)ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one in 36 ml of ethanol was added 24 ml of 0.5 M potassium carbonate. After the reaction was heated for 1 hour at 70°-80°, it was concentrated to a low volume and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The residue was crystallized from ether to give 0.9 g (67%) of cis-rac.-6-(hydroxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2(dimethylamino)ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one, mp 110°-111°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([OH:20])=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Reactant: Nc1ccccc1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with aniline there was obtained 3-(4-tert-butylbenzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][CH:7]=2)([CH3:3])[CH3:2]>[Ni].CO>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH2:13])=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)c1cc2cc(N)ccc2[nH]1
Yield: 41 %

Procedure:
A suspension of 2-isopropyl-5-nitro-1H-indole (100 mg, 0.49 mmol) and Raney Nickel (10 mg) in MeOH (10 mL) was hydrogenated under hydrogen (1 atm) at the room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by column (petroleum ether/ethyl acetate=5/1) to give 2-isopropyl-1H-indol-5-amine (35 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.69 (br s, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.58 (dd, J=2.4, 8.8 Hz, 1H), 6.07 (t, J=1.2 Hz, 1H), 3.55 (br s, 2H), 3.06-2.99 (m, 1H), 1.33 (d, J=7.2 Hz, 6H); MS (ESI) m/e (M+H+) 175.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CC[N:33](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH2:33])=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(N2N=C3c4ccc(C(N)=O)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.43 g, about 0.967 mmol), DIEA (0.77 mL, 4.45 mmol) and HATU (2.154 g, 5.665 mmol) were added to a mixed solvent of DMF (3.65 mL) and dichloromethane (6.8 mL) Ammonia gas was passed thereto. The mixture was stirred at room temperature for 24 hr. Water and dichloromethane were added. The mixture was extracted with dichloromethane. The combined organic phase was washed with water and saturated salt water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to produce a crude yellow solid, which was then washed with methanol and ethyl ether respectively to produce a purified product (0.18 g) in 44.3% yield.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH2:16][C:17](=[N:23][OH:24])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[OH:24][N:23]=[C:17]1[C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:16]1
Reactant: COC1=CC=C(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)CC1=NO
Solvent: O=C(O)C(F)(F)F
Product: COC1=CC=C(C[C@@H]2CNCCO2)CC1=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate (a) N-BOC-(R)-2-(3-hydroxyimino-4-methoxybenzyl)morpholine (85 mg, 0.24 mmol) was dissolved in TFA (20% v/v in dichloromethane, 5 mL total) and stirred at room temperature for 2 hrs. The reaction mixture was added directly to an SCX-2 column (1 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the crude product as a yellow solid (38 mg). The crude material was purified by HPLC to yield the desired morpholine example 25 as a white powder (12 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH3:20][O:19][N:18]([CH3:17])[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH3:15]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C

Procedure:
Commercially available (2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid (1.0 g, 4.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.47 g, 4.8 mmol) were dissolved in DMF (18 ml). O-benzotriazole-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (1.92 g, 5.06 mmol) and N,N-diisopropylethylamine (2.47 ml, 14.5 mmol) were added. The reaction was stirred at r.t. over night. The reaction was poured into a mixture of water and ethyl acetate. The mixture was shaken, the layers separated and the water layer washed twice with ethyl acetate. The collected organic phase was washed with a small portion of water and dried over sodium sulphate. The solvent was removed under educed pressure and the crude product was purified by flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C=O)C>[CH3:25]/[C:19](=[CH:5]\[C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)/[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(F)c(F)c1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of dry DMF (50 mL) under N2 was added 3,4,5-trifluorobenzaldehyde (4.26 g, 26.6 mmol) followed by ethyl 2-(triphenylphosphoranylidene)propionate (10.6 g, 29.3 mmol) in portions, keeping the solution at room temperature. After 1 hour, TLC (10% EtOAC in Hexanes) showed complete conversion, and the solvent was removed by rotary evaporation. The resulting material was brought up in 50 mL methyl t-butyl ether (MBTE) and the precipitate removed by filtration and washed with additional MBTE (3×50 mL). After concentration, the resulting filtrate was applied onto a silica gel column (25% EtOAc in hexanes) resulting in 6.0 g of the title compound (93%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:26])=[C:19](/[F:25])\[C:20](OCC)=[O:21])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:26])=[C:19](/[F:25])\[CH2:20][OH:21])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-3-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 71, 348 mg, 0.96 mmol) and diisobutylaluminum hydride (1 M dichloromethane, 2.9 mL, 2.88 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][C:12]([N:39]3[CH2:40][CH2:41][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH2:37][CH2:38]3)=[O:14])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC1CCC2(CC1)OCCO2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1CCC2(CC1)OCCO2)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (1,4-Dioxaspiro[4.5]dec-8-yl)-acetic acid (U.S. Pat. No. 5,124,332) (20.0 g, 99.8 mmol) and triethylamine (21 mL, 149 mmol) in 200 mL of methylene chloride (CH2Cl2) was cooled to 0° C. in an ice bath and treated with isobutyl chloroformate (13.98 mL, 107.8 mmol). After stirring for 10 minutes 1-(2-pyridinyl)piperazine (17.6 g, 108 mmol) is added in 50 mL of methylene chloride. The reaction is removed from the ice bath and stirred at room temperature for 24 hours. The reaction mixture is treated with 200 mL of a saturated sodium bicarbonate solution. The aqueous layer is separated and extracted with an additional 150 mL of methylene chloride. The combined organic fractions are dried over magnesium sulfate (MgSO4), and the solvent is removed under reduced pressure to give an oil which is triturated with diethyl ether (Et2O) to give 2-(1,4-dioxaspiro[4.5]dec-8-yl)-1-[4-(2-pyridinyl)-1-piperazinyl]-ethanone (22.7 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1>C1COCC1.C(O)(=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[N:3]=[C:4]([NH:17][CH3:18])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1

Procedure:
A solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (833 mg, 3.21 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (717.9 mg, 3.21 μmol) in THF (5.6 mL) and acetic acid (5.6 mL) was heated at 85° C. in a 350 mL high-pressure vessel overnight. The solvent was removed in vacuum and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, which was contaminated with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline. The material was triturated with methanol, cooled in the freezer and filtered. The residue was washed with freezing cold methanol and dried to give pure N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (673.5 mg, 47%) as light brown solid. LC-MS (M+H)+=446.9. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, d, J=1.8 Hz), 7.48 (1H, s), 7.27-7.33 (2H, m), 7.16-7.24 (3H, m), 6.96-7.07 (3H, m), 6.71 (1H, dd, J=8.4, 1.7 Hz), 4.50 (1H, br s), 4.20 (1H, s), 3.48 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.79 (3H, m), 2.01-2.13 (1H, m).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 207°-209° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OCC2C=CC=CC=2)=[O:12])=[CH:2]1.[BH4-].[Na+]>C(O)(C)C.O>[OH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(OCc1ccccc1)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 4 h

Procedure:
A suspension of benzyl 3-indolylglyoxylate (55.8 g.) and sodium borohydride (22.7 g.) in isopropanol (560 ml.) was heated to reflux over a period of 40 minutes and stirred at that temperature for 4 hours. After cooling the mixture was diluted with water (1.2 l.) and extracted with dichloromethane. The extract was washed with water and the solvent evaporated under reduced pressure to yield a viscous oil. This was distilled at 0.5 - 1 mm. pressure and the friction which distilled at a vapour temperature of 160°-190° was crystallised from toluene (100 ml.), giving the title compound as white crystals, mp. 57°-90°. Yield 24.3 g. (75.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([C:23]3[CH:24]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[N:20]=[C:21]([NH2:35])[N:22]=3)=[CH:26][CH:27]=2)[CH2:32]1)=[O:6]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)c3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 3-chlorobenzoyl chloride (Lancaster, Cat. #L01191) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=463.3/465.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[OH:27])[CH2:10][C@@H:9]2[OH:34])[CH2:4][CH2:3]1.[CH3:35][C:36]([CH2:38][C:39]([OH:41])=[O:40])=[O:37].[BH4-].[Na+]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[OH:27])[CH2:10][C@@H:9]2[OH:34])[CH2:4][CH2:3]1.[CH3:35][C:36]([CH2:38][C:39]([OH:41])=[O:40])=[O:37]
Reactant: C[C@]12C[C@H](N3CCC(=O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Agent: CC(=O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Yield: 69.5 %

Procedure:
2β-(4-Oxo-1-piperidinyl)-16β-(1-piperidinyl)-5α-androstane-3α,17β-diol-diacetate is reduced by using sodium borohydride as described in Example 1 to give the title compound in a yield of 69.5%, m.p.: 108°-110° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH3:12][Mg]Br>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([OH:11])[CH3:12])[CH:8]=2)[CH:3]=[N:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: C1CCOC1
Product: CC(O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of 1H-indazole-6-carbaldehyde (200 mg, 1.37 mmol) in THF (7 mL) at −78° C. was added methyl magnesium bromide (1.4 mL, 4.11 mmol) dropwise under argon. The solution was warmed to rt and quenched with saturated ammonium chloride (2 mL). The mixture was extracted into ethyl acetate (3×10 mL), dried over MgSO4 and concentrated. The yellow oil was purified by silica gel chromatography (EtOAc/Hex 4:1) to yield the title compound as a clear oil (135 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (s, 1H), 7.50-7.47 (m, 2H), 5.05 (q, 1H, J=7.4 Hz), 1.57 (d, 3H, J=7.2 Hz); MS ESI [M+H]+, calcd for [C9H10N2O+H]+ 163.1; found m/z 163.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([F:33])([F:32])[CH2:29][CH2:30][CH3:31])[CH:26]=3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:39]2[CH2:40][CH2:41][O:42][CH2:43][C@H:38]2[CH3:37])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([F:33])([F:32])[CH2:29][CH2:30][CH3:31])[CH:26]=3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CCl)CC2(C)C
Reactant: C[C@@H]1COCCN1
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=594.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]>C1COCC1.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([CH:16]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: O=C(Nc1cnc2[nH]ccc2c1)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1

Procedure:
3.85 g 2-Chloro-5-nitro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzamide in 600 ml THF were hydrogenated over 2.5 g platinum on carbon at atmospheric pressure over night at RT. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by chromatography on silica eluting first with ethyl acetate and finally ethyl acetate/methanol mixtures.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@@H:34]1[NH:38][CH2:37][C@@H:36]([NH:39]C(=O)OC(C)(C)C)[CH2:35]1>>[NH2:39][C@@H:36]1[CH2:37][N:38]([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=2)[C@@H:34]([CH2:33][OH:32])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN[C@@H](CO)C1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H](N)C[C@@H]3CO)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and ((3S,5R)-5-hydroxymethyl-pyrrolidin-3-yl)-carbamic acid, tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:32]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:3][CH2:4]4)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-({3 chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile and 306 mg (1.98 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 122 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-ethoxy-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 203-207° C.