Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][N:11]([CH2:23][CH2:24][CH2:25][CH2:26][Cl:27])[C:10]1=[O:28])(=O)C1C=CC=CC=1>N.CO>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:11]1[CH:12]=[C:13]([C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:14](=[O:15])[NH:9][C:10]1=[O:28]
Reactant: Cc1ncccc1-c1cn(CCCCCl)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: N
Solvent: CO
Product: Cc1ncccc1-c1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-(2-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione (Prep 47, 330 mg, 0.8 mmol) was dissolved in a solution of 3% NH3 in MeOH (15 mL). The mixture was stirred at room temperature for 3 hours, the solvent was then evaporated under vacuum. The residue was redissolved in MeOH and filtered on a SCX cartridge to give 220 mg of the title compound as a yellow oil (90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][NH:32][C@@H:31]([CH3:35])[CH2:30]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[F:36][C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42][CH2:43][C:44]2[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=2)=[CH:39][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:48][C:47]3[CH:50]=[CH:51][C:44]([CH2:43][CH2:42][O:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:53][CH:52]=4)=[CH:45][CH:46]=3)[C@@H:31]([CH3:35])[CH2:30]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1
Reactant: O=Cc1ccc(CCOc2ccc(F)cc2)cc1
Reactant: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN[C@@H](C)C4)cc3Cl)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(F)cc6)cc5)[C@@H](C)C4)cc3Cl)nc2)cc1
Yield: 61.6 %

Procedure:
To a CH2Cl2 (5 mL) solution of (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-[(3S)-3-methylpiperazin-1-yl]prop-2-en-1-one (0.50 g) and 4-[2-(4-fluorophenoxy)ethyl]benzaldehyde (298 mg) was added NaBH(OAc)3 (323 mg) at room temperature. The resultant mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 0/1) to give (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-[(3S)-4-{4-[2-(4-fluorophenoxy)ethyl]benzyl}-3-methylpiperazin-1-yl]prop-2-en-1-one as a yellow powder (451 mg).
Reaction SMILES: [Na].CN(C)[C:4]1[CH2:8][CH2:7][CH2:6][N+:5]=1[CH3:9].COS([O-])(=O)=O.[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[O:29])[CH3:18]
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=C1CCCN1C)c1ccc(Cl)cc1

Procedure:
Add [dropwise, with stirring, at 100° (bath temperature), in a stream of nitrogen] a solution of 9.6 g of sodium in 200 ml of ethanol to a mixture of 99 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate and 65 g of 4-chlorophenylacetic acid ethyl ester. Remove the alcohol from the reaction mixture by the stream of nitrogen. Continue stirring for a further 30 minutes at 100°; cool the reaction mixture; add 200 ml of water to the cooled reaction mixture; and then extract it with 5×100 ml of diethyl ether. Combine the ether extracts, dry the combined extracts over sodium sulfate, concentrate them and then remove a little excess 4-chlorophenylacetic acid ethyl ester by heating under a high vacuum to obtain a yield [86 g (94% of theory)] of crude title compound having a m.p. of 71°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10]C1C=C(C)C(C)=CC=1O>>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[OH:8]
Reactant: Cc1cc(O)c(Br)cc1C
Reactant: Cc1cc(O)ccc1F
Product: Cc1cc(O)c(Br)cc1F
Yield: 94 %

Procedure:
Prepared in 94% yield from 4-fluoro-3-methylphenol following the procedure for 2-bromo-4,5-dimethylphenol. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=8.5 Hz, 3H), 6.86 (d, J=7.0 Hz, 3H), 5.23 (s, 3H), 2.22 (d, J=1.8 Hz, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CS(O[CH2:11][C@@H:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:13])(=O)=O>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:13][C@@H:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:11]
Reactant: NCCCO
Reactant: C[C@@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: C[C@@H](CNCCCO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 3-Aminopropanol (5.00 kg, 66.6 mol) in acetonitrile (35 L) was added (S)—N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide (7.00 kg, 20.7 mol) was added at an internal temperature of 10° C. to 20° C. The reaction mixture was further stirred for 16 hours. After confirming the disappearance of the starting materials by TLC, the mixture was concentrated under reduced pressure. To the residue was added water. The resulting solution was acidified with 6 N hydrochloric acid until pH 4, and the insoluble materials were filtered off. The filtrate was made alkaline by adding potassium carbonate until pH 9 and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a pale yellow oil (6.10 kg, 92.8%).
Reaction SMILES: [NH2:1][C:2]1C(CCC)C(=O)C(CCC)[C:4](=[O:15])[C:3]=1[NH:16][C:17]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=O.[OH-].[K+].Cl.[CH2:32]([OH:34])C>>[CH2:2]([N:1]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[NH:1][C:2]=2[N:16]([CH2:17][CH2:19][CH3:20])[C:32]1=[O:34])[CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCC1C(=O)C(NC(=O)C2CCc3ccccc3C2)=C(N)C(CCC)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCCn1c(=O)c2nc(C3CCc4ccccc4C3)[nH]c2n(CCC)c1=O
Temperature: 70 °C

Procedure:
Dissolve 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2-amino-4,6-dioxo-3,5-dipropylcyclohex-1-enyl)amide (2.0 g, 5.2 mmol) in ethanol (50 ml), add 15% potassium hydroxide (50 ml) and heat to 70° C. for 4 hours. After cooling to 0° C., acidify the reaction with concentrated hydrochloric acid (13 ml). Add water (100 ml) and collect the resulting precipitate by suction filtration. Purify the white solid by flash chromatography (50% ethyl acetate/hexane) and triturate with 5% diethyl ether/hexane to provide, after drying under vacuum at 120° C. for 30 minutes the title compound (1.04 g), m.p. 202°-204° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:18][CH2:17][CH2:16][N:15]([C:19]3[CH:35]=[C:34]([CH3:36])[C:22]4[N:23]=[C:24]([C:26]5[C:27](Cl)=[N:28][CH:29]=[CH:30][C:31]=5I)[NH:25][C:21]=4[CH:20]=3)[CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].[O:38]1CCOCC1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:14][N:15]([C:19]3[CH:35]=[C:34]([CH3:36])[C:22]4[N:23]=[C:24]([C:26]5[C:27](=[O:38])[NH:28][CH:29]=[CH:30][C:31]=5[Cl:37])[NH:25][C:21]=4[CH:20]=3)[CH2:16][CH2:17][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Reactant: Cl
Reactant: C1COCCO1
Solvent: O
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 85 °C
Yield: 38 %

Procedure:
To a suspension of 2-benzyl-8-[2-(2-chloro-4-iodo-pyridin-3-yl)-7-methyl-3H-benzoimidazol-5-yl]-2,8-diaza-spiro[5.5]undecane (55 mg, 0.09 mmol) in H2O (0.75 mL) was added a solution of HCl in dioxane (4 M, 10 mL, 40 mmol). After it was heated at 85° C. for 18 h, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by chromatography (170:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (17 mg, 38%). 1H NMR (MeOH-d4) δ 1.23-1.35 (2H), 1.50-1.72 (6H), 2.09-2.31 (2H), 2.55 (s, 3H), 2.58-2.65 (2H), 2.88-3.72 (6H), 6.60 (d, J=6 Hz, 1H), 6.83 (s, 1H), 7.19-7.32 (6H), 7.52 (d, J=6 Hz, 1H). ESI-MS m/z 502 (MH+).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]2[C:52]3[C:47](=[C:48]([Cl:54])[CH:49]=[C:50]([Cl:53])[CH:51]=3)[CH2:46][N:45]([CH3:55])[CH2:44]2)[CH:38]=1)(=[O:36])=[O:35]>>[Cl:53][C:50]1[CH:51]=[C:52]2[C:47](=[C:48]([Cl:54])[CH:49]=1)[CH2:46][N:45]([CH3:55])[CH2:44][CH:43]2[C:39]1[CH:38]=[C:37]([S:34]([NH:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][S:7]([C:4]2[CH:5]=[CH:6][C:1]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]5[C:52]6[C:47](=[C:48]([Cl:54])[CH:49]=[C:50]([Cl:53])[CH:51]=6)[CH2:46][N:45]([CH3:55])[CH2:44]5)[CH:38]=4)(=[O:36])=[O:35])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:36])=[O:35])[CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(-c4ccc(S(=O)(=O)NCCOCCOCCOCCNS(=O)(=O)c5cccc(C6CN(C)Cc7c(Cl)cc(Cl)cc76)c5)cc4)cc3)c2)C1
Yield: 26.6 %

Procedure:
Compound 220 was prepared following the procedure outlined in Example 219 using biphenyl-4,4′-disulfonyl dichloride (16.1 mg, 0.0459 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 50 mg, 0.0917 mmol). Purification by preparative HPLC gave the title compound (16.7 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.96 (d, 4H), 7.88-7.85 (m, 5H), 7.78 (s, 2H), 7.61 (t, 2H), 7.47 (d, 2H), 6.78 (s, 2H), 4.74-4.69 (m, 3H), 4.45 (d, 2H), 3.88-3.83 (m, 2H), 3.62-3.59 (m, 2H), 3.55-3.53 (m, 9H), 3.52-3.43 (m, 17H), 3.13 (s, 6H), 3.11-3.03 (m, 8H). MS (m/z): 1371.02 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@@H:10]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][CH:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@@H](C1)OCC(=O)N2Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2C(C1)OCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 1-benzyl-2-oxooctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (126 g, 346 mmol) in anhydrous THF (2 L) was added borane methylsulfide complex (109 mL, 1.038 mol) drop wise at 0° C. The mixture was stirred at room temperature overnight. Methanol (300 mL) was added to the mixture at room temperature and heated to reflux for 1 h. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford tert-butyl 1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a mixture of trans diastereomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CCN(C(C)C)C(C)C>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: CN(C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(CC(=O)N(C)C)C1
Temperature: 70 °C
Reaction time: 20 h
Yield: 4.3 %

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-chloro-N,N-dimethylacetamide (43 μL, 0.414 mmol) and DIPEA (215 μL, 1.24 mmol) in IMS (2 mL) was stirred in a sealed vial at 70° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) followed by HPLC purification (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-50% 0.1% NH4OH in acetonitrile/water). The product containing fractions were concentrated in vacuo affording 151 as a white solid (8 mg, 4%). LCMS: RT 1.87 min [M+H]+ 448.1. 1H NMR (DMSO, 400 MHz): δ 8.24 (1H, s), 8.10 (1H, s), 7.95 (1H, bs), 7.73-7.68 (1H, m), 7.65-7.58 (1H, m), 7.21-7.12 (2H, m), 4.66-4.55 (1H, m), 3.22 (2H, s), 3.06-2.88 (6H, m), 2.80 (3H, s), 2.75-2.68 (1H, m), 2.21 (1H, t, J=11.73 Hz), 2.10-1.96 (1H, m), 1.77-1.64 9 4 H, m), 1.55 (1H, bd, J=13.18 Hz), 1.13-0.98 (1H, m)
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:30]=[C:31]([Br:35])[C:32]([Cl:34])=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:42](=[O:44])[CH3:43])[CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=2)[C:9]2[CH:30]=[C:31]([Br:35])[C:32]([Cl:34])=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c(Cl)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (1.40 g, 2.38 mmol) and pyridine (5.00 ml) was treated with acetic anhydride (5.00 ml) via dropwise addition. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50.0 ml), washed with 1.00N HCl (2×50.0 ml) and brine (3×150 ml). Dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient eluent, 0-40% ethyl acetate in hexane) provided the titled compound (1.28 g, 85%) as white foamy solid. MS (ES+): 629, 631 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.CO>C(OCC)C>[N+:9]([C:5]1[C:6]([OH:8])=[N:7][C:2](/[CH:1]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][C:4]=1[OH:12])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)nc(/C=C/c2ccccc2)nc1O
Temperature: 90 °C
Yield: 63.1 %

Procedure:
A mixture of 2-methyl-5-nitropyrimidine-4,6-diol (4.7 g, 27.5 mmol) and benzaldehyde (42 mL, 414 mmol) was treated with piperidine (21.3 mL, 215.3 mmol). The reaction mixture was heated to 90° C. for 2 hrs. The temperature was then increased to 120° C. for 30 min. After cooling the reaction mixture to ambient, methanol (10 mL) and diethyl ether (200 mL) were added sequentially. The resulting solid was collected by filtration and washed with 5% aqueous hydrochloric acid to give 5-nitro-2-[(E)-2-phenylvinyl]pyrimidine-4,6-diol (4.5 g). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, 1H, J=16.4 Hz), 7.15 (m, 2H), 7.54 (m, 3H), 6.81 (d, 1H, J=16.4 Hz). MS (m/z) 260 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][C:10]([OH:19])=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[N:20]1([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([O:30][CH2:31][CH2:32]O)=[CH:28][CH:27]=2)[CH:24]=[CH:23][N:22]=[CH:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][O:19][C:10]3[N:11]=[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[CH:34][CH:35]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: Oc1cnc(-c2ccccn2)c(-c2ccccn2)n1
Reactant: OCCOc1ccc(Cn2ccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncc(OCCOc3ccc(Cn4ccnc4)cc3)nc2-c2ccccn2)nc1
Yield: 44 %

Procedure:
5,6-Di(2-pyridyl)-2-pyrazinol (1.21 g), 2-[4-(1H-imidazolylmethyl)phenoxy]-1-ethanol (1.05 g), and triphenylphosphine (1.27 g) were dispersed in tetrahydrofuran (30 mL). A 40% solution (2.10 g) of diethyl azodicarboxylate in toluene was added dropwise to the dispersion under ice cooling, and the resultant mixture was allowed to react overnight, while the temperature of the mixture was gradually elevated to room temperature. After completion of reaction, ethyl acetate was added to the reaction mixture, and the ethyl acetate layer was washed with water. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column and recrystallized from ethyl acetate, to thereby yield 960 mg of Compound (1B) of the present invention as pale yellow crystals (yield 44.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:28]
Reactant: CCOC(=O)c1cc2c(N)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(NC(=O)CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 65 %

Procedure:
Ethyl 4-amino-N-(3,4-dichlorobenzyl)indole-2-carboxylate (2.03 g), chloroacetyl chloride (0.5 ml) and triethylamine (4.0 ml) were stirred in dichloromethane (50 ml) for 16 hours. The reaction was washed with water, dried (MgSO4) and concentrated in vacuo. The residue was triturated with toluene to give the product as a pale grey solid (1.61 g, 65%); NMR d (CD3SOCD3) 1.28 (t, 3H), 4.30 (q, 2H), 4.40 (s, 2H), 5.81 (s, 2H), 6.88 (dd, 1H), 7.30 (m, 3H), 7.50 (d, 1H), 7.76 (s, 1H), 7.78 (d, 1H), 10.19 (brs, 1H); M/z (−) 439 (M+), 4.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[OH:17][C@H:14]1[C@@H:15]([CH3:16])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[C:12](=[O:20])[C:13]1([CH3:18])[CH3:19]
Reactant: COc1cc(N2C(=O)C(C)(C)C(=O)C2C)ccc1C#N
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)C(C)(C)[C@@H](O)[C@H]2C)ccc1C#N

Procedure:
Using 2-methoxy-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.551 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 75 mg, 74%).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 66) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 501.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH2:30][CH2:31][CH2:32][OH:33].C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[N:11]=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:30][CH2:31][CH2:32][OH:33])=[O:27])=[CH:28][CH:29]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)NCCO)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoic acid (100 mg) obtained in Step A of Example 231, 2-aminoethanol (0.022 mL) and triethylamine (0.050 mL) in DMF (3 mL) was added 2-(7-azabenzotriazol-1-yl)-1,1,3,3-hexafluorophosphate (137 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (105 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:31])([CH3:30])[C:14]([NH:16][NH:17][C:18]1[N:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=O)=[CH:8][CH:7]=2>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([C:14]1[N:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)([CH3:31])[CH3:30])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(C(C)(C)C(=O)NNc3ccc(-c4ccccc4)nn3)cc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(C(C)(C)c3nnc4ccc(-c5ccccc5)nn34)cc2c1

Procedure:
A solution of 2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide (270 mg, 653 μmol) in TFA (2 mL) was heated to 150° C. in microwave (6 bar; 20 W) for 2 h. LCMS suggests very good conversion: 89425-17-1. Reaction concentrated under reduced pressure then partitioned between CHCl3/IPA (50 mL) and 1M NaOH (50 mL). Aqueous further extracted with CHCl3/IPA (15 mL) and combined organics dried over MgSO4, concentrated, then dissolved in ACN (2 mL). Crystallized solid washed with ACN (1 mL) and dried under reduced pressure. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C24H21N5O: 395.