Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([C@@H:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][N:37]2C(OC(C)(C)C)=O)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([C@@H:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][NH:37]2)=[O:35])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:31][CH2:32]3)[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Yield: 57.3 %

Procedure:
To a 250 mL round-bottomed flask equipped with stirring was added tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)-methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step c) (1.9 g, 2.5 mmol) followed by a saturated soln of HCl in EtOAc (150 mL). The mixture was stirred at RT for 1 h then concentrated in vacuo to 75 mL, providing a white precipitate. The precipitate was collected by filtration and dried in vacuo to provide the HCl salt as a white solid (0.93 g). MS (ESI, pos. ion) m/z: 649 (M+1). Calc'd for C35H41ClN4O4S: 648.25.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Product: CC(=O)c1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from Intermediate 2 and (3-acetylphenyl)boronic acid (Sigma Aldrich Company Ltd.) using the method of Example 1; mass spectrum (API+): Found 358 (MH+), C20H23NO3S requires 357; 1H-NMR (400 MHz, CDCl3): 1.42 (6H, d, J=7 Hz), 2.66 (3H, s), 2.99 (2H, m), 3.20 (1H, m), 3.35 (2H, m), 4.29 (2H, m), 7.32 (1H, m), 7.46 (2H, m), 7.56 (1H, m), 7.76 (1H, m), 7.92 (1H, m), 8.14 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=C[N:6]3[N:12]=[CH:13][N:14]=[C:5]3[C:4]=2[CH:3]=1.N>Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[N:14]=[CH:13][NH:12][N:6]=2)[CH:3]=1
Reactant: Fc1ccc2ncn3ncnc3c2c1
Agent: Cl
Agent: N
Product: Nc1ccc(F)cc1-c1nc[nH]n1
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
4. 2.3 g of 9-fluoro-1,2,4-triazolo[1,5-c]quinazoline in 40 ml of 6N hydrochloric acid are stirred at 95° C. for 1 h. and then cooled in an ice bath. The reaction solution is poured into 30 ml of 25% aqueous ammonia and stirred in an ice bath for 10 min. The crystals are filtered off, washed with 30 ml of ice-cold water and dried in a vacuum. 2.0 g of 4-fluoro-2-(1H-1,2,4-triazol-3-yl)aniline of m.p. 142.5°-144.5° C. are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:19]([CH2:22][CH3:23])[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C.O>[CH2:24]([N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@@H:19]([CH2:22][CH3:23])[CH:20]=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
A 2M solution of oxalyl chloride in dichloromethane (3.18 ml, 6.36 mmol) was cooled to −78 0° C. and diluted with dry dichloromethane (20 ml) under dry nitrogen. A solution of dimethylsulfoxide (1 g, 12.72 mmol) in anhydrous dichloromethane was added dropwise to the cooled stirred solution. The reaction was stirred for a further 1 h after completion of addition. A solution of (S)-2-(dibenzylamino) butan-1-ol (1.43 g, 5.3 mmol) in dichloromethane was added over 5 minutes. After 10 minutes, diisopropylethylamine (2.73 g, 21.2 mmol) was added. The reaction was allowed to warm to room temperature and left stiffing for 1 h. It was cooled to 0° C. and ethyl acetate/water (50 ml: 50 ml) was added. The organic layer was washed with water (50 ml), brine (50 ml) dried (MgSO4) and concentrated. The product was purified by flash silica column chromatography (ethyl acetate:Hexane 1:4) to provide the pure product (1.28 g, 90.5%). δH (250 MHz, CDCl3) 0.88 (3 H, t, J 7.5, CHCH2CH3), 1.77-1.54 (2 H, m, CH2CH3), 2.99 (1 H, t, J 7.5, CHCH2CH3), 3.74-3.57 (4 H, m, 2×CH2Ph), 7.31-7.11 (10 H, m, 2×C6H5) 9.64 (1 H, s, CHO); δC (250 MHz, CDCl3) 203.9 (CO), 139.33 (2×C), 128.99 (4×CH), 128.45 (4×CH), 127.3 (2×CH), 68.46 (CH), 54.85 (CH2), 17.44 (CH2), 11.83 (CH3); m/z 268.2 (M+H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CN(C)C=O
Product: Clc1ccc2c(-n3cncn3)ccnc2c1
Yield: 112.8 %

Procedure:
1.98 g of 4,7-dichloro-quinoline and 1.38 g of 1H-1,2,4-triazole are reacted in 10 ml of dimethyl formamide and worked up as described in Example 1. 2.6 g of 4-(1H-1,2,4-triazole-1-yl)-7-chloro-quinoline (Substance 2) are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH3:21])[S:17](=[O:23])(=[O:22])[N:16]([CH2:24][CH3:25])[CH2:15]2)=[CH:10][C:9]=1Br)(C)(C)C.[CH3:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:24]([N:16]1[CH2:15][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N:32]3[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]3)[CH:10]=2)[CH2:19][N:18]([CH2:20][CH3:21])[S:17]1(=[O:23])=[O:22])[CH3:25]
Reactant: CCN1CC(c2ccc(NC(=O)OC(C)(C)C)c(Br)c2)CN(CC)S1(=O)=O
Reactant: CC1CCNCC1
Product: CCN1CC(c2ccc(N)c(N3CCC(C)CC3)c2)CN(CC)S1(=O)=O
Temperature: 25 °C

Procedure:
The title compound is prepared from [2-bromo-4-(2,6-diethyl-1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and 4-methylpiperidine following the literature procedure of Buchwald (Org. Lett., 4, 2885-8 (2002)). The residue obtained is purified by silica gel chromatography with an appropriate solvent mixture. After isolation, removal of the BOC protecting group from the resulting intermediate is carried out by stirring at RT in TFA-DCM (1:2), monitoring by TLC for completion, and then concentration in vacuo.
Reaction SMILES: S(C1C=CC=CC=1)([O-])(=O)=O.[CH3:11][S:12]([CH2:15][C:16]([OH:18])=O)(=[O:14])=[O:13].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([C:47]2([C:64]([F:67])([F:66])[F:65])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:63][NH:62][CH2:61]3)[O:56][CH2:55]4)[CH2:48]2)[CH:42]=[C:43]([Cl:46])[C:44]=1[F:45]>C(OCC)(=O)C>[Cl:46][C:43]1[CH:42]=[C:41]([C:47]2([C:64]([F:65])([F:67])[F:66])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:61][N:62]([C:16](=[O:18])[CH2:15][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:63]3)[O:56][CH2:55]4)[CH2:48]2)[CH:40]=[C:39]([Cl:38])[C:44]=1[F:45]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)COC43CNC3)=NO2)cc1Cl
Reactant: CS(=O)(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 35 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Alternatively, the besylate salt of the chiral 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]can be coupled with methanesulfonylacetic acid using n-propylphosphonic anhydride via a simplified one-pot process instead of the CDI two-pot method. Triethylamine (0.825 g, 1.3 eq.) was added drop-wise over 1 minute at about 18-22° C. to methanesulfonylacetic acid (0.615 g, 1.3 eq.) and chiral-5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran] (Preparation 8, 2.1 g, 3.39 mmol) in 9.3 mL ethyl acetate (EtOAc). The addition funnel was rinsed with 0.5 mL EtOAc and the resulting mixture stirred for a minimum of 2 hours and cooled to <10° C. To this mixture, 50% n-propylphosphonic anhydride in EtOAc (4.313 g, 2.0 eq) was added drop-wise over 15 minutes at <10° C. The addition funnel was then rinsed with 1.5 mL EtOAc. The reaction mixture was warmed to 35° C. and stirred overnight. (HPLC >97% with <1% starting material). To the reaction was added 1.0 g Celite filter aid and filtered through a 1 g celite plug in a 15 mL coarse frit glass funnel and rinsed with 4 mL EtOAc (2×). In process chiral HPLC was 98.8% S-enantiomer and 1.2% R-enantiomer; HPLC >97%. Filtrate was washed with 4 mL water (3×), 4 mL 10% NH4Cl, 4 mL water and the organic layer concentrated to the amorphous S form of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone (foam, 70-80% yield). 1H NMR, 600 MHz (d6-CDCl3) δ ppm: 7.65 (m, 5H), 5.19 (br s, 2H), 4.70 (m, 2H), 4.48 (d, 1H), 4.38 (d, 1H), 4.12 (d, 1H), 3.90 (d, 2H), 3.72 (d, 1H), 3.23 (s, 3H); m/z (CI) 581 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:11]([O:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(COCCC2OCCO2)cc1
Temperature: 25 °C

Procedure:
2-(2-Hydroxyethyl)-1,3-dioxolane (7.0 g, 58.3 mmol) was dissolved in dried tetrahydrofuran (distilled from sodium) (200 ml). Sodium hydride (2.0 g, 66.7 mmol, 80%) was added and the mixture was stirred at ambient temperature until gas evolution was completed. Tetrabutylammonium iodide (0.22 g, 0.6 mmol) and benzyl bromide (9.7 g, 56.8 mmol) were added, and the mixture was stirred for 24 hours at ambient temperature. Diethyl ether (100 ml) was added and the mixture was washed with water (3×100 ml), dried with magnesium sulphate and 2(2-benzyloxyethyl)-1,3-dioxolane was distilled as a colourless oil. Yield 9.3 g (75%) b.p. 75°-78° C. (0.02 mm Hg). The structure was confirmed by 1H NMR and 13C NMR.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetic acid chlorocarbonyl-methyl ester the title to compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:19].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:19][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: [I-]
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
1.8 g of 4-chloromethyl-5-methyl-2-naphthalen-2-yloxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.7 g of 4-iodomethyl-5-methyl-2-naphthalen-2-yloxazole as a light-yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][CH:4]=1.C1CCN2C(=[N:16]CCC2)CC1.O>CN1C(=O)CCC1>[NH:16]1[C:5]2[C:6](=[CH:7][N:8]=[CH:9][CH:4]=2)[CH:10]=[CH:11][C:3]1=[O:2]
Reactant: CNCc1ccc(OC)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccc2cnccc2[nH]1
Yield: 173.7 %

Procedure:
A solution of Example A18 (22 g, 65.7 mmol), (4-methoxy-benzyl)-methyl-amine (14.9 g, 98.5 mmol) and DBU (15 g, 98.5 mmol) in NMP (120 mL) was heated at 160° C. for 5 h. The mixture was poured into 200 mL of water while stirring and the resulting solids were collected by filtration, washed with water, dried and then washed with Et2O to give 3-(5-amino-2,4-difluoro-phenyl)-1-ethyl-7-[4-methoxy-benzyl)-methyl-amino]-1H-[1,6]naphthyridin-2-one (25 g, yield 85% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.51 (s, 1H), 7.80 (s, 1H), 7.19-7.17 (d, J=8.7 Hz, 2H), 7.06 (t, J=10.2 Hz, 1H), 6.90-6.81 (m, 3H), 6.32 (s, 1H), 5.02 (s, 2H), 4.86 (s, 2H), 4.19 (q, J=6.9 Hz, 2H), 3.72 (s, 3H), 3.14 (s, 3H), 1.14 (t, J=6.9 Hz, 3H); MS (ESI): m/z 451.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=O.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:12])[O:11][CH2:14][C:15]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)c(F)c3)C(=O)OC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHIMICAL) (10 g) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Example 9, Step 1) (17.3 g) in acetonitrile (200 mL) at room temperature was added slowly triethylamine (20.2 mL). After 1 h at room temperature, the mixture was cooled in an ice bath and treated with 17.4 mL of DBU. After 2 h at 0° C., the mixture was treated with 200 mL of 1N HCl and the product was extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was applied on top of a silica gel plug (sintered glass funnel) eluted with 75% EtOAc/hexane, giving after evaporation of the solvent and swish in ethyl acetate, 10 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>CC(C)=O>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: COc1ccc2c(Cl)nncc2c1C#Cc1ccncc1
Temperature: 85 °C
Yield: 62 %

Procedure:
A suspension under N2 of 6-methoxy-5-pyridin-4-ylethynyl-2H-phthalazin-1-one (2.26 g,), prepared as described in example 141, in POCl3 (40 ml) was heated for 3 hours at 85° C., then dried. The residue was taken up in a saturated NaHCO3 solution up to alkalinity, then filtered and extracted with ethyl acetate. The solid was dissolved in a CH2Cl2/CH3OH/ethyl acetate mixture, dried over Na2SO4 and filtered. The solution was joined to the previous organic phase and dried to give a residue which was taken up in acetone and filtered yielding 1.5 g of the title compound (yield: 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7](=[O:9])[NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccn1
Reactant: CN(C)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CN(C)CCNC(=O)c1nc(N)sc1-c1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of ethyl 2-amino-5-(2-pyridyl)-4-thiazolecarboxylate (2.49 g) in ethyleneglycol (10 ml) were added N,N-dimethylethylenediamine (1.76 g) and 36% hydrochloric acid (0.5 ml) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (50 ml), adjusted to pH 8 with aqueous potassium carbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from acetonitrile to give 2-amino-4-[N-[2-(N,N-dimethylamino)ethyl]carbamoyl]-5-(2-pyridyl)thiazole (2.0 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][O:24][CH3:25]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][O:24][CH3:25])[CH2:10]1
Reactant: COCCBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Preparation according to Example 43: Enantiomer E2 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1-bromo-2-methoxyethane (0.255 mL, 2.7 mmol). Stirred 1 h at ambient temperature. Addition of 1-bromo-2-methoxyethane (0.05 mL, 0.53 mmol), stirred at 40° C. for 2 min. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1). Yield: 0.32 g. [α]D=−20.8° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 146.7° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 2), 212 (bp), 182 (56), 141 (9), 127 (12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+].C(O)CO>[Cu]>[CH2:9]([S:11][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:10]
Reactant: Nc1ccc(I)cn1
Reactant: CC[S-]
Agent: [Cu]
Agent: [Na+]
Solvent: OCCO
Product: CCSc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 26 h
Yield: 77.8 %

Procedure:
2-Amino-5-iodo-pyridine (2.20 g; 10 mmol), sodium ethanethiolate 80% (1.7 g; 16 mmol) and copper powder (190 mg; 3.00 mmol) were loaded into a 100 mL round bottom flask under nitrogen. Ethylene glycol (40 mL; 0.25 mol) was added and the solution stirred at 150° C. for 26 h. The cooled solution was filtered and partitioned between ethyl acetate and water twice. The organic layer was dried over barium oxide, filtered and the solvent removed in vacuo to afford 1.2 g (yield 76%) of product as yellow oil. 1H-NMR (300 MHz; CDCl3), δ 8.06 (1H, d, 4JHH=2.1 Hz, Ar—H), 7.48 (1H, dd, 3JHH=8.7 Hz, 4JHH=2.4 Hz, Ar—H), 6.42 (1H, dd, 3JHH=8.7 Hz, 5JHH=0.6 Hz, Ar—H), 2.68 (2H, q, 3JHH=7.3 Hz, CH2), 1.15 (3H, t, 3JHH=7.2 Hz, CH3).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]=O>C(O)=O>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][CH3:35])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CCN2CCCC(CC3CCCCC3)C2)c2cc(N)ccc2n1C(=O)c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CNc1ccc2c(c1)c(CCN1CCCC(CC3CCCCC3)C1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of the 1-benzoyl-3-[2-(3-cyclohexylmethylpiperidino)ethyl]-5-amino-2-methylindole described above in Example 95 with formaldehyde and formic acid affords 1-benzoyl-3-[2-(3-cyclohexylmethylpiperidino)ethyl]-5-methylamino-2-methylindole.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:30])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[F:30])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1
Yield: 64.8 %

Procedure:
Using pyrrolidin-2-one (51 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[OH-].[Na+]>O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][O:4][CH2:1][C:2]#[CH:3]
Reactant: C#CCO
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOCCCCBr
Reaction time: 8 h

Procedure:
A mixture of 2-propyn-1-ol (10 g), 1,4-dibromobutane (60 ml), 50% aqueous sodium hydroxide (60 ml) and TAB (2 g) was stirred vigorously overnight. Water (250 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were dried and concentrated to a yellow oil which was purified by FCC eluting with H→H/ER (19:1) to give the title compound as a colourless oil (19.7 g), t.l.c. (H-ER 19:1) Rf 0.37.
Reaction SMILES: C(Cl)Cl.[CH:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][O:18][CH3:19])[CH:8]=1)([CH3:6])[CH3:5].CO.[CH3:22][Si](C=[N+]=[N-])(C)C>CC(O)=O.CCCCCC>[CH:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:22])=[O:12])=[C:9]([O:16][CH2:17][O:18][CH3:19])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCOc1cc(C(C)C)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
Into methylene chloride (40 mL) was dissolved 4-isopropyl-2-methoxymethoxy-benzoic acid (6.0 g, 26.8 mmol). Methanol (10 mL) was added, followed by the dropwise addition of 2 M hexane solution of trimethylsilyldiazomethane (14.7 mL). After 2 h, HOAc (0.5 mL) was added and the solvent was removed under vacuum, giving the title compound as an oil, which was used in next step without further purification.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[Li+].[O-2].[Al+3].[O-2].[O-2].[Al+3].[C:19](=[O:21])=[O:20]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:19]([OH:21])=[O:20])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Al+3]
Agent: [Li+]
Agent: [O-2]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 190 °C
Yield: 85 %

Procedure:
p-Acetaminophenol 15 g, lithium hydroxide 60 g, and aluminum oxide 45 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 3.0 MPa and heated to 190° C., maintained for 2 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve lithium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 99% and the yield is 85%.