Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([C:27](=O)[CH3:28])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([CH:27]([NH2:36])[CH3:28])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethanone (0.094 g, 0.22 mmol), ammonium acetate (0.17 g, 2.2 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.56 mL, 0.56 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product. LCMS calculated for C22H25ClF2N3O (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[O:22][CH3:23].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[C:5]([O:22][CH3:23])[CH:6]=1)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OCCCNC(=O)OC(C)(C)C)ccc1C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
4-(3-(t-Butyloxycarbonylamino)-propyloxy)-2-methoxybenzoic acid methyl ester (2.63 g, 7.76 mmol) from Step 2 was dissolved in MeOH (25 mL) and heated with 1N NaOH (15 mL, 15 mmol)) at 50° C. for 18 h. The reaction was cooled to ambient temperature and 5% aqueous citric acid (10 mL) was added. The mixture was extracted with EtOAc (3×75 mL). The combined EtOAc phases were washed with water (2×50 mL) and brine (50 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(3-(t-butyloxycarbonylamino)propyloxy)-2-methoxybenzoic acid as a white foam (95% yield).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCOCC2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCOCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-morpholinobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 411.21 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:29][N:30]1CCCC1=O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[N:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][C:4]=4[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Br)cc1C
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C#N)cc1C
Temperature: 100 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
A mixture of 1-(5-bromo-3-methylpyridin-2-yl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (463 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol) and zinc cyanide (176 mg, 1.5 mmol) in 1-methyl-2-pyrrolidinone (2.0 mL) was stirred at 100° C. for 14 hr. The mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/isopropyl ether to afford the title compound (195 mg, 48%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[C:4]([F:12])[CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](CO)c1ccc(Br)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenyl)propan-1-ol (800 mg, 3.43 mmol), phthalimide (554 mg, 3.77 mmol), and triphenylphosphine (1.34 g, 5.14 mmol) in THF (2 mL) was added DIAD (1 mL, 5.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h and evaporated under vacuum. Flash chromatography of the residue afforded the desired product (1 g, 81%) as a white solid ESI MS m/z 363 [C17H13BrFNO2+H]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][C:60]=1[F:61]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:57]=[CH:56][C:55]([F:54])=[C:60]([F:61])[CH:59]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-fluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 24 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=2:3) to obtain the title compound (81%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:21]([O:24][C:25](Cl)=[O:26])[CH2:22][CH3:23]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:25]([O:24][CH2:21][CH2:22][CH3:23])=[O:26])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 5.0 g tert-butyl 1-piperazinecarboxylate in 64 ml dichloromethane were added 8.2 ml triethylamine. The solution was cooled to 0° C. and 3.3 ml propylchloroformate were added dropwise at this temperature. After stirring for 12 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was directly used in the next reaction step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:19])=[C:9]([NH2:20])[N:8]=2)[CH:2]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>O1CCOCC1>[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:20][C:9]3=[N:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)[CH:11]=[C:10]3[N:19]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cc(-c2ccncc2)c(-c2cccnc2)nc1N
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc3cc(-c4ccncc4)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 96 h
Yield: 13.9 %

Procedure:
A sealed tube containing 3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 2,148 mg, 0.56 mmol), 4-fluorobenzaldehyde (57.0 μL, 0.53 mmol) and dioxane (3 mL) was filled with air and heated to 100° C. for 6 days. Then, the solvent was removed and CH3CN (2 mL) followed by Yb(OTf)3 were added, and the reaction mixture was stirred for 4 days at room temperature. Afterwards, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (CH2Cl2/EtOH/aq NH3 100:8:1) to afford the title compound as a white solid (27 mg, 13%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[N:39]O)[NH2:38])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:39]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(Cc1ccc(F)cc1)=NO
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(Cc3ccc(F)cc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′hydroxyethanimidamide were reacted according to the General Method 1. Yield: 61 mg (57% of theory)
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH:13]=[CH:12][N:11]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[N:8]([C:20](=[O:22])[CH3:21])[CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)(=O)C.[BH4-].[Na+].[Cl-].[NH4+]>CO.ClCCl>[C:20]([N:8]1[C:9]2[C:10]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:11]3[CH:12]=[CH:13][C:14]=2[C@@H:5]([OH:4])[CH2:6][C@H:7]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC1=CC(c2ccccc2)N(C(C)=O)c2c1ccn1c(C)c(C)nc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)C[C@H]1c1ccccc1
Reaction time: 3 h
Yield: 75.2 %

Procedure:
12.2 g (32.5 mmol) of rac-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naphthyridine are dissolved in 50 ml of methanol and 10 ml of dichloromethane. 5.0 g (132 mmol) of sodium borohydride are then introduced at 0° C. over a period of 2 h. After 3 h, 30 ml of saturated ammonium chloride solution are added. The reaction mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate and evaporated. The residue is crystallized using diethyl ether. 8.2 g (75%) of the title compound are isolated as a colorless solid (m.p. 217° C.).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]1[N:12]=[N:13][N:14]([CH3:16])[N:15]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][CH2:9][C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:11]1[N:12]=[N:13][N:14]([CH3:16])[N:15]=1
Reactant: Cn1nnc([C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1nnc([C@H](CO)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of 166 mg of tert-butyl [(1R)-2-(benzyloxy)-1-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate, 40 mg of 10% palladium-carbon (hydrous), and 8 ml of ethanol was stirred at room temperature for 18 hours under a hydrogen atmosphere of 4 atm. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain 106 mg of tert-butyl [(1R)-2-hydroxy-1-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[C:19]=1[CH3:20].Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[C:19]([CH3:20])[C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cc3c(C)c(OC)ccc3o2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 200 °C
Yield: 75 %

Procedure:
The crude 5-Methoxy-2-(4-methoxyphenyl)-4-methylbenzofuran 136 (0.134 g) was taken into a sealed tube along with enough pyridine hydrochloride to fill the tube halfway and heated at 200° C. for 2.5 hours. The reaction was dissolved into a mixture of ethyl acetate and 1 N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics was washed with 1 N HCl (1×), water (1×) and then dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography on silica gel, using 30% ethyl acetate in hexanes as the eluent to yield the desired product (0.090 g, 23.4% based on starting 4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran from two runs) as a tan powder: Mp. 221-222° C.; 1H NMR (DMSO-d6) δ 9.81 (s, 1 H), 8.94 (s, 1 H),) 7.70 (d, 2 H, J=8.6 Hz,), 7.16 (d, 1 H, J=8.9 Hz), 7.14 (s, 1 H), 6.86 (d, 2 H, J=8.6 Hz), 6.72 (d, 1 H, J=8.6 Hz), 2.27 (s, 3 H); MS 241 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[N:18]([N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:22]=2)[CH:19]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH:12][S:23]([C:21]1[N:22]=[C:17]2[N:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]2[N:20]=1)(=[O:24])=[O:25]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: Cc1cnc2nc(S(=O)(=O)Cl)nn2c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2ncc(C)cn2n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methyl 3-methylanthranilate (2.1 g, 13 mmol) was dissolved in 4 ml pyridine and 6-methyl-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonyl chloride was added. After a mild exothermic reaction subsided the reaction mixture was stirred at 50° C. for 24 hours. The pyridine was removed by evaporation at reduced pressure and the residue was treated with in 10% aqueous sodium bicarbonate. Insoluble material was collected by filtration, washed with ether and dried to yield 2.9 (63%) of the desired product as a solid, m.p. 198.5°-205° C. An analytical sample was prepared by recrystallization from ethanol to yield a crystalline solid, m.p. 208.5°-210.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([S:33]Cl)[CH:29]=[C:30]([Cl:32])[CH:31]=1.O>C(#N)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:33][C:28]2[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClSc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1c[nH]c(COCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
2-Benzyloxymethyl-4-isopropyl-1H-imidazole (7) (550 mg, 2.4 mmol), described as Reference Example 1 of WO 96/10019 was dissolved in a mixture of triethylamine 360 mg (3.6 mmol) and acetonitrile 4 ml. To the solution was added 3,5-dichlorobenzenesulfenyl chloride (3) 930 mg (4.4 mmol) at room temperature. The mixture was stirred for 30 minutes at room temperature and water (15 ml) and toluene (15 ml) were added thereto. The toluene layer was separated, washed with water 10 ml twice, and concentrated under reduced pressure. The obtained yellow oil was crystallized with diisopropyl ether 10 ml, filtered, and dried to yield the objective (8) 800 mg as a pale yellow crystal. Yield 82%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[N:14]([C:2]2[C:3]3[CH:10]([CH3:11])[S:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC1SCc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 120 °C
Yield: 63.4 %

Procedure:
To a solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (5 g, 27 mmol) and 2-(S)-methyl-4-Boc-piperazine (5.4 g, 27 mmol) in NMP (20 mL) was added DIEA (5 mL, 29 mmol). The mixture was heated to 120° C. for 24 hours. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×200 mL). The organic phase was dried and concentrated to afford (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (6 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 8.55 (s, 1H), 4.81 (m, 1H), 4.45 (m, 1H). 4.18 (m, 3H), 3.90 (m, 1H), 3.75 (m, 1H), 3.44-3.29 (m, 2H), 2.96 (m, 1H), 1.52 (m, 12H), 1.14 (d, J=6.4 Hz, 3H). MS (APCI+) [M+H]+ 351. The residue was purified by chiral HPLC separation (OD 250×20 mm; acetonitrile, 2 mL/min). The first peak (RT=3.93 min) was (S)-tert-butyl 3-methyl-4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate and the secondary (RT=4.26 min) was (S)-tert-butyl 3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH:33](N(CC)C(C)C)(C)[CH3:34].ICC>>[CH2:33]([N:24]1[CH2:25][CH2:26][CH:21]([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:27])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1)[CH3:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCNCC3)ncc2c1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCC(C(=O)Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.4 %

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide (110.6 mg, 0.1936 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N,N-diisopropylethylamine (0.1 mL, 0.574 mmol) and iodoethane (19.0 uL, 0.238 mmol). The reaction was stirred at room temperature for 19 hours, and then N,N-diisopropylethylamine (0.1 mL) and iodoethane (30 uL, 0.375 mmol) were added. After an additional 4 hours, the mixture was evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 31.4 mg (41%) of 1-ethyl-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide. LCMS (ESI): RT (min)=4.370, M+H=392.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.19 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 3.53 (unresolved, 2H), 3.08 (unresolved, 2H), 2.83 (unresolved, 3H), 2.25 (s, 3H), 2.07 (unresolved, 2H), 1.90 (unresolved, 2H), 1.22 (unresolved, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[C@H:50]([CH2:51][CH2:52][C:53](=[O:57])[CH:54]=2)[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH:48]2O)([CH3:46])[C:44](=[O:59])[CH2:43][CH2:42]1>C(OCC)(=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[C@H:50]([CH2:51][CH2:52][C:53](=[O:57])[CH:54]=2)[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][C@@H:48]2[F:12])([CH3:46])[C:44](=[O:59])[CH2:43][CH2:42]1
Reactant: C[C@]12CC(O)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
3.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene and, drop by drop, 4 ml of perfluorobutane-1-sulfonic acid fluoride are added to 6.7 g of 7α-(9-chlorononyl)-11-hydroxy-estr-4-ene-3,17-dione in 35 ml of ethyl acetate at 0° C. After 2 hours, it is diluted with ethyl acetate, washed several times with 2N hydrochloric acid and neutralized with saturated sodium bicarbonate solution and water. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. Yield: 6.2 g of 7α-(9-chlorononyl)-11β-fluor-estr-4-ene-3,17-dione as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:12]=2)=[O:10])=[CH:3][CH:2]=1.C(O)(C)C.[H][H]>[Ni].O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[CH:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ccc(Cn2cc(C(=O)C(=O)Nc3ccncc3)c3ccccc32)cc1
Reaction time: 3 h

Procedure:
A mixture of 200 mg of Raney nickel in 50 ml of dioxane is treated with a suspension of 320 mg (0.8 mmol) of N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxyl-amide in a solvent mixture of 150 ml of dioxane and 20 ml of isopropanol. Hydrogen is passed into this suspension with shaking at a gas pressure of 5 bar and the temperature is kept at 30-35° C. After about 3 hours, a further 400 mg of Raney nickel are added and the hydrogenation is continued at 35° C. and 5 bar for a further 8 hours with vigorous shaking. The catalyst is filtered off under an N2 atmosphere, the filtrate is concentrated to dryness in vacuo and the residue is dried in vacuo at 40° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]=[C:11]=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11]([NH:10][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:12])=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)OCO3)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 3,4-methylenedioxyphenyl isocyanate and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 11.