Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=O)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:19][O:20][C:21]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:9](=[O:11])[C@H:8]([NH:7][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:27]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A mixture of (R)-Isopropoxycarbonylamino-phenyl-acetic acid (0.74 g), (L)-proline methyl ester hydrochloride (0.51 g), N-methyl morpholine (1.00 mL) and 1.00 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (ethyl acetate/isohexane=3/1) to give 0.95 g (91%) of the title compound as a colorless oil. (+)-APCI-MS: 349 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]Br>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1cnc2ccc(C(=O)c3cnc4ccc(Cl)nn34)cc21
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cnc2ccc(C(C)(O)c3cnc4ccc(Cl)nn34)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(3-methyl-3H-benzoimidazol-5-yl)-methanone (Stage 185.4, 560 mg, 1.796 mmol) was dissolved in THF (50 mL) with heating under Argon. The solution was let to cool down and methylmagnesium bromide (3 M, 0.719 mL) was added. The mixture was stirred at rt for 1 h. To complete the reaction, more methylmagnesium bromide (3 M, 0.30 mL) was added and the RM was stirred 30 min longer. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dried under vacuum overnight to afford the title compound as an off white foam (tR 1.84 min (conditions 8), MH+=328).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[C:9](C(OCC)=O)[N:8]([CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[N:7]=1)=[O:5])[CH3:2].O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[C:9]2[C:20](=[O:22])[NH:19][CH2:18][CH2:17][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(CCNC(=O)OC(C)(C)C)c(C(=O)OCC)c1I
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CCOC(=O)c1nn2c(c1I)C(=O)NCC2

Procedure:
The compound was prepared from 1-(2-tert-butoxycarbonylamino-ethyl)-4-iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester using the method described in the preceding example 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14]C(=O)C)=[C:8]([C:12]=1[CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl>[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([C:12]=1[CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A solution of 10.2 g (43 mmoles) of 5-nitro-6-methyl-2-acetylaminobenzoic acid in 100 mL of 2M NaOH was heated to reflux for two hours. The resultant red solution was allowed to cool to near room temperature, then transferred to a beaker sitting in an ice bath. The solution was slowly acidified with 2N HCl to a pH of approximately 4-5 when a voluminous yellow solid separated out. In all, approximately 110 mL of 2N HCl was added. The collected yellow solid was dried in a vacuum oven for 3 hours at 75 degrees. 4.0 g (48% yield) 5-nitro-6-methyl-2-aminobenzoic acid was obtained. NMR(DMSO-d6): 2.45 (s,3H), 3.35(bs,2H), 6.68(d,1H,J=9.0 Hz), 7.86(d,1H,J=9.0 Hz). MS(m/z): 196(M+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.Cl[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:14])[N:15]([O:17][CH3:18])[CH3:16])[N:10]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287c (10.4 g, 1.0 eq., 41.9 mmol), tert-butyl 2-chloroethylcarbamate (37.7 g, 5.0 eq., 210.0 mmol), Na2CO3 (22.3 g, 5.0 eq., 210.0 mmol), and DMF (100 mL). The reaction mixture was stirred at 110° C. overnight. After cooling to room temperature, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 287d (10.8 g, 66%) as yellow oil. MS-ESI: [M+H]+ 392.0
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COCCCCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.7 %

Procedure:
2-Chloro-3-nitropyridine (3.54 g) and 4-methoxybutan-1-amine hydrochloride (3.12 g) were suspended in 2-propanol (100 ml), diisopropylethylamine (11.6 μl) was added and the mixture was heated under reflux with stirring for 4 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (4.26 g).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH:13]=[CH2:14]
Reactant: O=C(CBr)c1cccnc1
Reactant: C=CCNCC=C
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCN(CC=C)CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
2-Bromo-1-(3-pyridyl)ethanone hydrobromide (10 g, 23.49 mmol) is added portion wise over 5 minutes to a stirred solution of diallylamine (5.2 mL, 42.29 mmol) and diisopropylethylamine (10.24 mL, 58.73 mmol) in tetrahydrofuran (150 mL) at 0° C. The resulting mixture is stirred at 0° C. for 1 hour. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (300 mL). The layers are separated and the aqueous phase is re-extracted with dichloromethane (300 mL). The combined organic layers are dried over magnesium sulfate and the solvents are removed under reduced pressure to give a crude product which is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (4.75 g, 93%). ES/MS (m/e): 217 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: CC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(4-methylcyclohexyl)-3-piperidinecarboxamide (192.2 mg, 0.427 mmol), 5 mL of EtOH, Hunig's base (0.298 mL, 1.706 mmol), and hydrazine anhydrous (0.080 mL, 2.56 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow suspension as well as some black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid being heavier than the yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum. The yellow residue was dissolved in CH3OH, and purified by HPLC to afford the light yellow title compound (95 mg). LC-MS (ES) m/z=509 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.81-1.04 (m, 4H), 1.08-1.37 (m, 6H), 1.40-1.86 (m, 10H), 2.16-2.44 (m, 1H), 2.92 (m, 1H), 3.78 (m, 1H), 5.38 (s, 2H), 6.08 (s, 2H), 6.56 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.67-7.82 (m, 2H), 7.88-7.99 (m, 1H), 8.16 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc([N+](=O)[O-])cc32)CC1
Yield: 24.6 %

Procedure:
6-Nitro-1H-indazole (12.26 mmol, 2 g), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (12.26 mmol, 3.42 g) and potassium carbonate (24.52 mmol, 3.39 g) were combined and heated to 100° C. in N,N-dimethylformamide (40 mL) for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from 20% ethyl acetate/heptane to 60% ethyl acetate/heptane) to afford the title compound (1.045 g). MS (ESI) m/z 347.2 [M+H]+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1.C(N(C(C)C)C(C)C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].Cl>C(Cl)Cl.C(Cl)Cl.CO>[CH3:47][S:48]([NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1)(=[O:50])=[O:49]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CNS(C)(=O)=O)c2)nc1OC

Procedure:
A solution of 70 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride, product of example 30 b), in CH2Cl2 (5 ml), was treated at RT with 50 mg of N-ethyldiisopropylamine, 15 mg of methanesulfonyl chloride and then refluxed for 18 h until the reaction was complete according to TLC analysis (CH2Cl2/MeOH: 95/5). The mixture was poured into cold diluted HCl and the product extracted into CH2Cl2. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/MeOH: 95/5). Combination of the purified fractions and evacuation in vacuo afforded 5-methyl-pyridine-2-sulfonic acid [2-[2-(methanesulfonylamino-methyl)-pyridin-4-yl]-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a light yellow solid. ISN mass spectrum, m/e 585 (M−1 calculated for C25H26N6O7S2: 585).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[C:4]=1[C:5]#[N:6].C=O.[C:31]([BH3-])#N.[Na+]>CO>[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:31])[CH2:24]2)[C:4]=1[C:5]#[N:6]
Reactant: [BH3-]C#N
Reactant: N#Cc1c(C2CCCNC2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred solution of 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinonitrile hydrochloride (200.0 mg, 0.50 mmol) in MeOH were added formaldehyde (0.5 mL) and sodium cyanoborohydride (40.8 mg, 0.65 mmol) and stirred for 2 hrs at room temperature. The reaction was quenched by an addition of water, extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and dried. The crude product was purified by preparative silica gel TLC (5% MeOH in dichloromethane) to give 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinonitrile as a yellow solid. (28.5 mg, yield 15%)
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.[C@@H:29]([N:33]([CH2:44][C:45]1[N:54]=[C:53](Cl)[C:52]2[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][CH2:48][C:47]=2[N:46]=1)C(=O)OCC1C=CC=CC=1)([CH2:31][CH3:32])[CH3:30]>>[CH3:57][C:50]1([CH3:56])[CH2:49][CH2:48][C:47]2[N:46]=[C:45]([CH2:44][NH:33][C@H:29]([CH2:31][CH3:32])[CH3:30])[N:54]=[C:53]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:52]=2[CH2:51]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CC[C@H](C)N(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)C(=O)OCc1ccccc1
Product: CC[C@H](C)NCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and (S)-benzyl sec-butyl((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.61-8.44 (m, 1H), 8.12-7.93 (m, 1H), 7.71 (d, 1H), 7.54 (dd, 1H), 7.03 (d, 1H), 4.67 (s, 2H), 4.35-4.27 (m, 2H), 3.92-3.84 (m, 2H), 3.56 (q, 2H), 2.69 (t, 3H), 2.54 (s, 2H), 2.45 (s, 3H), 2.42-2.30 (m, 1H), 1.59 (t, 2H), 1.27 (dd, 2H), 1.18-1.04 (m, 1H), 0.87 (s, 6H), 0.83 (d, 3H), 0.70 (t, 3H); MS (EI) for C31H39N7O: 526 (MH+).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14]I>>[C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: O=C(O)c1ccc2ccccc2n1
Product: COC(=O)c1ccc2ccccc2n1

Procedure:
Reaction of 10.0 g of quinaldic acid with 5.4 ml of methyliodide by the method described in Example 97f) for 20 h at room temperature and purification of the crude product by FC over 80 g of silica gel (mobile phase C) gives methyl quinaldate as a white solid: Rf (50:50:6 mixture of hexane, ethyl acetate and glacial acetic acid)=0.65.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=O)[CH:10]=[C:9]2[CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH2:11][CH:10]=[C:9]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CO
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1=CCN(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
11 ml (147 mmol) of thionyl chloride are added dropwise over approximately 30 minutes to a stirred suspension of 12.5 g (49 mmol) of 6-chloro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 150 ml of methanol. The mixture is stirred for 17 hours at room temperature and the solvent is driven off under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulphate, the organic phase is filtered and the filtrate is condensed. 11.16 g of expected product are obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4].[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.14 g), rhodium(I) acetate (0.57 g) and toluene (30 mL) was added dropwise a solution of ethyl diazoacetate (2.30 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.24 g, 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:23])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[Cl:23][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)cc3)c(Cl)c2)cc1
Yield: 48.9 %

Procedure:
2.00 g (5.40 mmol) of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine, 1.50 g (6.00 mmol) of 4-octyloxybenzeneboronic acid, 0.07 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.3 g (12.00 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 20 ml of toluene, 10 ml of ethanol and 10 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated, and the product is purified by chromatography (silica gel/dichloromethane), giving 1.38 g of 3-chloro-2,5-di(4-octyloxyphenyl)pyridine. ##STR24##
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:42](OC)=[O:43])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([OH:41])([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=2.O.[NH2:47][NH2:48]>>[OH:41][C:13]([C:9]1[CH:8]=[CH:7][C:6]2=[CH:5][C:4]3[C:42](=[O:43])[NH:47][NH:48][CH2:2][C:3]=3[CH:12]=[C:11]2[CH:10]=1)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: NN
Reactant: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1CBr
Solvent: O
Product: CC(C)C(O)(c1ccc2cc3c(cc2c1)CNNC3=O)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 3-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.95 g) and hydrazine monohydrate (0.50 ml), 7-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-3,4-dihydrobenzo[g]phthalazin-1(2H)-one (0.05 g) was obtained as a colorless amorphous solid and 7-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]benzo[g]phthalazin-1(2H)-one (5 mg) was obtained as a colorless amorphous solid.