Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][C:26]3[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]2=[O:35])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:31]([F:34])([F:33])[C:28]1[O:27][C:26]([CH2:25][N:14]2[C:15]3[CH:16]=[C:17]4[O:24][CH2:23][CH2:22][O:21][C:18]4=[CH:19][C:20]=3[C:12]3([C:3]4=[CH:4][C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[C:2]4[O:1][CH2:36]3)[C:13]2=[O:35])=[CH:30][CH:29]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)OCCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one was obtained (76%) as a colorless solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 6.75-6.67 (m, 2H), 6.49-6.43 (m, 2H), 6.37-6.31 (m, 1H), 6.22-6.16 (m, 1H), 4.87 (ABq, 2H), 4.69 (ABq, 2H), 4.26-4.04 (m, 8H); 13C NMR (75 MHz, CDCl3 δ 177.2, 155.0, 152.0, 151.9, 144.6, 144.0, 140.1, 138.3, 135.2, 124.3, 120.9, 113.7, 112.6, 112.6, 111.5, 109.1, 99.3, 98.9, 80.0, 64.6, 64.5, 64.0, 63.9, 57.8, 37.0; MS (ES+) m/z 501.9 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(Cl)Cl.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:4]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH2:3][CH2:2][O:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:11][CH:12]=1)#[N:15]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(CCO)n2ccnc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC(c1ccc(C#N)cc1)n1ccnc1
Reaction time: 4 h

Procedure:
The 4-(3-hydroxy-1-imidazol-1-yl-propyl)-benzonitrile (1.4 gm, 6.16 mmol) was suspended in 2:1 methylene chloride: THF (100 mL) under argon and cooled to 0° C. in an ice bath. Methanesulfonylchloride (1 mL, 12.4 mmol) was added followed by diisopropylethylamine (3.22 mL, 18.5 mmol). The reaction was stirred for 4 hours and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel using using 1:3 ethyl acatate: hexanes. The desired fractions were concentrated in vacuo to give the desired product.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22].C(O)(=O)C>C(O)C>[SH:3][C:2]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[C:14](=[O:13])[C:15]2[C:16](=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:22]=1
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: COc1ccccc1N=C=S
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-Isothiocyanato-2-methoxy-benzene (0.76 mL, 5.45 mmol) was added to a solution of 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 5.45 mmol) and acetic acid (1.5 mL) in ethanol (10 mL), and heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and diluted with ethanol. The precipitated solid was filtered, washed with ethanol and dried to afford 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (1.0 g, 62%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[NH:18]C(=O)C>>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:4](=[O:6])[C:3]3[C:2]([NH:18][C:17]=2[CH:16]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(=O)Nc1cccc(N)c1
Product: Nc1ccc2c(=O)c3ccc([N+](=O)[O-])cc3[nH]c2c1

Procedure:
The compound S3 (Y═NH) was prepared using 2-chloro-4-nitrobenzoic acid and 3′-aminoacetanilide in the same way as S3 (Y═O). 1H-NMR (DMSO-d6) δ 11.54 (s, 1H), 8.32 (d, J=8.8, 1H), 8.26 (d, J=2.0, 1H), 7.92 (d, J=8.8, 1H), 7.86 (d, J=2.0, 8.4, 1H), 6.60 (dd, J=2.0, 8.8, 1H), 6.43 (d, J=2.0, 1H), 6.36 (bs, 2H). ESI-MS m/z (M+H) calc'd: 256.1, found 256.1.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][NH:24][CH2:23]4)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH3-][C:45]#N.[Na+].CC(O)=O.C=O>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][N:24]([CH3:45])[CH2:23]4)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CNC2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CN(C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (8.3 mg, 0.0136 mmol) in MeOH (0.2 mL), was added NaCNBH3 (1.0 mg, 0.0163 mmol), AcOH (3.85 uL, 0.068 mmol) and formaldehyde (38%) (1.3 uL, 0.0176 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was washed with sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-methyl-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc. 625.2; found=624.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:34])[CH3:33]>>[ClH:1].[CH2:32]([O:34][C:29](=[NH:30])[C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:24]([F:31])[CH:25]=1)[CH3:33]
Reactant: N#Cc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reactant: CCO
Product: CCOC(=N)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Product: Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
4-Chloro-N-(4-cyano-2-fluoro-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide (0.23 g, 0.49 mmol) was suspended in dry ethanol (10 ml) and cooled to 0° C. Dry HCl gas was gently bubbled over 30 min into this suspension. The light red reaction mixture was stirred at room temperature for 20 h. A clear yellow solution resulted which was concentrated under reduced pressure and the crude was used directly in the next step: 0.28 g; MS: m/e=516.2 (MH−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][O:16]C(Cl)Cl>O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[CH:15]=[O:16]
Reactant: COc1ccc([N+](=O)[O-])cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 42 h

Procedure:
p-Nitroanisole (25 g., 0.163 mole) was dissolved in 400 ml. of methylene chloride and cooled to 10° C. Titanium tetrachloride (61.8 g., 36 ml., 0.326 mole) was added, followed by 1,1-dichloromethyl methyl ether added over 2 minutes. The mixture was warmed to room temperature and stirred for 42 hours. The reaction mixture was diluted with 1 liter of ice and water and extracted with three 500 ml. portions of methylene chloride. The organic extracts were combined, washed with two portions of water and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (20 g.). The oil was chromatographed on 600 g. silica gel, using 2:1 methylene chloride: hexane as eluant, collecting 15 ml. fractions, and monitoring by tlc. Clean product fractions 79-185 were combined and evaporated to yield 2-methoxy-5-nitrobenzaldehyde (3.8 g.; m.p. 87-89, literature m.p. 89°-90°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: Nc1nc(C2CC2)c(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)c(C2CC2)nc1N
Reaction time: 5 h

Procedure:
Cuprous iodide (11.23 mg, 0.059 mmol) was added to a mixture of 5-bromo-6-cyclopropyl-3-iodopyridin-2-amine (1 g, 2.95 mmol), triethylamine (13.4 g, 132.75 mmol) and THF (4 mL) and the resultant mixture was purged with nitrogen gas. Ethynyltrimethylsilane (347.7 mg, 3.54 mmol) and Pd(PPh3)2Cl2 (41.36 mg, 0.059 mmol) were added and purged with argon. The resultant mixture was stirred under argon atmosphere for 5 hours. The mixture was concentrated to residue. Residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate and concentrated to get solid which was further purified on column (SiO2) using 15% ethyl acetate in hexane as eluent. This afforded 1.2 g (crude) of the pure compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)(=O)[CH3:2].[NH2:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O>C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:26][C:24]1[CH:25]=[C:18]2[C:19]([CH:20]=[CH:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]4[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=4[CH:16]=3)=[N:17]2)=[CH:22][CH:23]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Temperature: 200 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 5-acetyl-2-methoxycarbonylbenzofuran (0.57 g), 2-amino-4-chlorobenzaldehyde (0.40 g) and p-toluenesulfonic acid monohydrate (0.04 mg) was stirred at 200° C. for 3 hours. After being cooled, the resulting mixture was dissolved in chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrated under reduced pressure to give 7-chloro-2-(2-methoxycarbonylbenzofuran-5-yl)quinoline (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]1([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNCC1(N2CCN(C)CC2)CCCCC1
Solvent: c1ccccc1
Product: CN1CCN(C2(CN(C)C(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 23.5 %

Procedure:
A solution of 3,4-dichlorobenzoylchloride (0.61 g.,) in benzene (10 ml) was added dropwise over 25 mins. to a stirred solution of 1-[1-(methylaminomethyl)cylcohexyl]-4-methyl piperazine (1) (0.65 g.). The mixture was then heated on a steambath for 1 hr. and the mixture was evaporated to dryness. The residue was dissolved in hot light petroleum (60°-80°) and decolourised with charcoal. The solid which separated was crystallised from light petroluem (60°-80°) to give 3,4-Dichloro-N-methyl-N-[[1-(4-methyl-1-piperazinyl)cyclohexyl]methyl]benzamide (0.27 g., 23%) m.p. 126°-129°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][O:20][C:21]=1[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:19][O:20][C:21]=1[CH3:22])=[O:14]
Reactant: Cc1cc(C(=O)Cl)c2cc(F)ccc2n1
Reactant: Cc1onc(-c2ccccc2)c1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2c(-c3ccccc3)noc2C)c2cc(F)ccc2n1
Temperature: 70 °C
Yield: 61.9 %

Procedure:
6-Fluoro-2-methylquinoline-4-carbonyl chloride (100 mg) and 4-amino-5-methyl-3-phenylisoxazole (200 mg) were dissolved in dichlorormethane (10 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/1) to give 6-fluoro-2-methyl-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.58 (s, 3H), 2.76 (s, 3H), 7.14 (s, 1H), 7.44 (s, 1H), 7.49 (m, 4H), 7.67 (m, 2H), 7.82 (dd, J=2.7 and 9.9 Hz, 1H), 8.07 (dd, J=5.7 and 9.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-111.63; LCMS: ret. time: 21.32 min.; purity: 99.44%; MS (m/e): 362.06 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]([CH2:21][OH:22])[CH2:19][O:18][C:17]2=[O:23])=[CH:12][CH:11]=1>C(N(CC)CC)C>[CH3:1][S:2]([O:22][CH2:21][CH:20]1[CH2:19][O:18][C:17](=[O:23])[N:16]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)(=[O:4])=[O:3]
Reactant: O=C1OCC(CO)N1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Methanesulfonyl chloride (3.0 g) was added dropwise to a dichloromethane (50 ml) solution of 5.30 g of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl alcohol obtained in Reference Example 17 and 8.5 ml of triethylamine with ice-cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by chloroform-ethanol gradient elution to give 6.50 g of the title compound (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O>CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[CH2:28][O:24][CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COCc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (144.5 mg) in DMF (3 mL) was added 60% sodium hydride (36.9 mg) at 0° C., and the mixture was stirred for 30 min. 3-(Bromomethyl)benzonitrile (90 mg) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (162 mg).
Reaction SMILES: NC(N)=O.C=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12]([OH:15])(=[O:14])[CH3:13]>>[NH:7]([CH2:13][C:12]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: NC(N)=O
Product: O=C(O)CNCC(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A 2 L autoclave was charged with urea (V) (60 g, 1.0 mole), Co(OAc)2.4H2O (66 g, 0.26 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately one hour, rapid gas uptake was observed. The reaction mass was cooled to 85° C. and the feed gas was changed to a CO:H2 (90:10) composition. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 16 mL/min. The reaction was stirred at 85° C. for 90 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and concentrated to an oil under reduced pressure. The oil was treated with 2 L of 10% HCl at 100° C. for two hours. This resulted in a 13% yield of (XIV) and 5% glycine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.[OH-:32].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:32])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (51.2 mg), toluene (0.47 ml), water (0.2 ml), tetra-n-butylammonium bromide (49.9 mg), and sodium hydroxide (54.3 m) were added under a nitrogen atmosphere at room temperature, and stirred at 120° C. for 4 hours. Then, the organic layer was removed. 3.5% by weight of hydrochloric acid (4 ml) was added to the mixture at room temperature, and extracted with tert-butyl methyl ether. Then, the organic layer was concentrated under reduced pressure to give 40.8 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20](=[O:21])[CH2:19][O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)nc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 53.5 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-ol (340 mg, 1.62 mmol) was treated with 60% NaH in oil (130 mg, 3.25 mmol) and tert-butyl bromoacetate (1.2 mL, 8.13 mmol) as above to yield 280 mg of a yellow solid following flash chromatography. ES-MS calcd for C15H21N3O5 (m/e) 323.35, obsd 324.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][CH2:12][OH:13].CC(C)([O-])C.[Na+]>C1COCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([O:13][CH2:12][CH2:11][O:10][CH3:9])=[CH:7][N:6]=1
Reactant: Brc1cnc(Br)cn1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 2,5-dibromopyrazine (22-1, 20.0 g, 84.1 mmol), 2-methoxyethanol (6.40 g, 84.1 mmol), and sodium tert-butoxide (11.3 g, 118 mmol) in 168 mL of THF was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with ethyl acetate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:hexanes=1:5 as eluant) to give 2-bromo-5-(2-methoxyethoxy)pyrazine (22-2, 17.2 g) as yellow oil in 88% yield: 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=1.0 Hz, 1 H), 8.07 (d, J=1.0 Hz, 1 H), 4.46 (t, J=5.0 Hz, 2 H), 3.74 (m, 2 H), 3.43 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30]>C(#N)C>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:2]=1[Cl:1])=[O:8]
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccccc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 142 mg of 2-(1H-benzimidazol-2-yl)phenylamine in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([NH:37][C@H:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39](=[O:40])[C@H:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])[CH3:42])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 83 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and (R)-2(tert-butoxycarbonylamino)propanoic acid (32 mg, 0.17 mmol). Yield 25 mg (34%).