Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25]CC)=[O:24])[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[Li+]>C1COCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3CC(=O)O)cc2)c1
Reaction time: 2 h
Yield: 117.8 %

Procedure:
To a stirred solution of 36 (1.3 g, 2.0 mmol) in THF (10.0 mL) at room temperature, was added a solution of lithium hydroxide (103 mg, 4.0 mmol) in water (10.0 mL) and stirring continued for 2 h. On completion, the solvent was removed and the reaction mixture diluted with water (20 mL) and washed with ether (30 mL×3). The aqueous layer was acidified with 1N HCl and extracted with 10% methanol in dichloromethane (50 mL×3). Combined organic layer was washed brine, dried over sodium sulphate and concentrated. The crude product after ether and pentane washing afforded 38 (1 g, 83%). LCMS: 425.15 (M+1)+; 1H NMR (DMSO-ds, 400 MHz) δ 13.3 (s, 1H), 8.24 (s, 2H), 8.12 (d, 1H, J=8 Hz), 7.78 (t, 1H, J=8 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.04 (s, 1H), 5.13 (s, 1H), 3.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:15]I.OS([O-])(=O)=O.[K+]>O>[OH:1][C:2]1[C:7]([I:15])=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccnc(O)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: Oc1ccnc(O)c1I
Temperature: 100 °C

Procedure:
A mixture of 2,4-dihydroxypyridine (1.0 eq), K2CO3 (1.0 eq), and water was stirred at 100° C. so that it became homogeneous. With continued stirring and heating, I2 (1.0 eq) was added in portions, causing the evolution of gas. When the solid I2 was consumed, the mixture was cooled and acidified with aqueous KHSO4 (1.0 eq), generating a precipitate. The precipitate was collected by filtration, rinsed with water, and stored under high vacuum, to give 2,4-dihydroxy-3-iodopyridine.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC1C=C(Cl)C=C(Cl)C=1[C:19](C1C(Cl)=CC(Cl)=CC=1Cl)([C:23]([O-])=[O:24])[C:20]([O-])=[O:21]>COCCOCCOC>[OH:24][C:23]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:9])[NH:1][C:20](=[O:21])[CH:19]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C([O-])C(C(=O)[O-])(c1c(Cl)cc(Cl)cc1Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: COCCOCCOC
Product: CCOC(=O)c1c(O)cc(=O)[nH]c1C

Procedure:
A solution of ethyl 3-aminocrotonate (12.6 g, 97.5 mmol) and of intermediate 11 in diglyme (400 ml) was heated at 100° C. for 3 hours during which the product separated out. After cooling, diethylether (1.5 l) was added and the desired intermediate 12 was filtered (14.2 g, 75%). m.p. 243–245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:25]=[N:26][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:28][CH:29]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Ic1cnc(N2CCOCC2)nc1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cnc(N3CCOCC3)nc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-(5-iodopyrimidin-2-yl)morpholine (Intermediate-5, 0.139 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.035 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.67 (br s, 4H), 3.76 (br s, 4H), 7.47-7.71 (m, 5H), 7.98 (d, J=9.0 Hz, 2H), 8.58 (s, 2H), 12.69 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:11]=2[C:10]=1[C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:11]=2[C:10]=1[C:25](=[O:27])[NH2:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc2cc(-c3ccc(F)cc3)ccc2c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1sc2cc(-c3ccc(F)cc3)ccc2c1C(N)=O
Yield: 32.7 %

Procedure:
To a solution of 1g (150 mg, 0.38 mmol) in DMF (3 mL) was added 1,1′-carbonyl diimidazole (125 mg, 0.78 mmol). The resultant solution was stirred at room temperature for 1 h and mixed with ammonium hydroxide (37%, 5 mL). The mixture was diluted with brine solution (10 mL) and extracted with ethyl acetate (20 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided the title compound (48 mg, 32%) as a white solid: MS (ES) m/z 387 (M+H)+; 1H NMR (400 MHz, CDCl3) δ11.14 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=4.4 Hz, 1H), 7.61 (m, 3H), 7.18 (m, 2H), 5.87 (brs, 2H), 1.59 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]([O:14]C)=[O:13])[CH2:6]1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]1
Reactant: COC(=O)C1CC(C)CN(Cc2ccccc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(C(=O)O)CN(Cc2ccccc2F)C1
Reaction time: 8 h

Procedure:
To methyl 1-(2-fluorobenzyl)-5-methylpiperidine-3-carboxylate (0.5 mmol), LiOH (1 mmol) in 2 ml THF/H2O (1:1) was added. The reaction was stirred overnight. The solvent was removed under vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(CCN)cc1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Triethylamine (1.89 g, 18.68 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (2.00 g, 9.32 mmol) in toluene (50 ml). The mixture was stirred at room temperature. Then, 4-butoxyphenethylamine (2.16 g, 11.18 mmol) was added. After stirring for 18 hours, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (2.00 g, 58%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[C:9]([F:19])[CH:8]=1.[C:20](=[O:22])=[O:21]>C1COCC1.O>[CH:15]1([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1COC1CCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COC2CCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane; 7.0 ml) was added to a solution of 4-bromo-1-cyclobutoxymethyl-2-fluorobenzene (2.6 g) in THF (50 ml) at −78° C. After 15 minutes, dry ice (4.4 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 224.23 (C12H13FO3); MS (ESI): 225 (M+H+) was obtained in this way.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][N:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:28])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 100 °C
Yield: 88 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added (±)-1-benzoyl-4-piperidinecarbohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 221 mg of the title compound (88%) as a yellow solid in 94.1% purity by HPLC (Rt: 3.93, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=1[C:38]([O:40][CH3:41])=[O:39])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.CO>N.[Ni]>[CH3:41][O:40][C:38](=[O:39])[C:31]1[CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=[CH:35][C:30]=1[CH2:29][N:18]([CH2:17][C:9]1[NH:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)c1cc(CN)ccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Yield: 70.8 %

Procedure:
A solution of 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (710 mg, 1.29 mmol) in saturated NH3(g)/MeOH (25 mL) was shaken at room temperature with a suspension of Raney® nickel (1.2 g) under hydrogen atmosphere (50 psi) for 17 h. The catalyst was removed by filtration over celite, and the filtrate was concentrated in vacuo. The crude material was filtered through silica gel (20:1:1 CH2Cl2/MeOH/NH4OH) to give a white foam (416 mg, 71%).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2.C1(C(N)C2CCCCC2)CCCCC1.Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>C1COCC1>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2)=[N:1]1
Reactant: O=Cc1ccc2n[nH]cc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2H-Indazole-5-carbaldehyde (Stage 150.5, 770 mg, 5.27 mmol) was dissolved in THF (54 mL) and dicyclohexylmethylamine (1.37 mL, 6.32 mmol) was added. After dropwise addition of (2-chloromethoxy-ethyl)-trimethyl-silane (1.21 mL, 6.32 mmol), the RM was stirred for 48 h at rt. It was then taken into EtOAc and washed successively with 0.5 M aqueous NaOH solution and brine. The organic layer was dried on Na2SO4 and evaporated and the residue purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=100:0->70:30) to afford white crystals of the title compound (tR 7.14 min (conditions 3), MH+=277).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2,3-dimethylphenyl)piperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [C:1]([CH:20]=[CH2:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:22][OH:23]>>[C:1]([CH2:20][CH2:21][CH2:22][OH:23])([C:4]([C:7]([C:10]([C:13]([C:16]([F:17])([F:18])[F:19])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CO
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
After confirming disappearance of C6F13CH═CH2 by gas chromatography, the reaction was terminated by cooling to obtain a reaction liquid. From the obtained reaction liquid, majority of methanol was distilled off under reduced pressure, and then, the reaction liquid was washed with water to remove the remaining methanol thereby to obtain 430 g of C6F13CH2CH2CH2OH having a purity of 92.8%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:53][CH:54]=[CH2:55])[CH2:13][C:14]([NH:16][C@@H:17]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][C:39]=1[F:52])[C:18]([N:20]([CH2:29][CH:30](OCC)OCC)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=1)=[O:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:30]2[CH2:29][N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=3)[C:18](=[O:19])[C@H:17]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:40][C:39]=3[F:52])[N:16]2[C:14](=[O:15])[CH2:13][N:12]1[CH2:53][CH:54]=[CH2:55])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN(CC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)N(Cc1cccc(F)n1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(OCc4ccccc4)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
A mixed solution of (2S)-2-(2-(((benzylcarbamoyl)amino)(prop-2-en-1-yl)amino)acetamido)-3-(4-(benzyloxy)-2-fluorophenyl)-N-(2,2-diethoxyethyl)-N-((6-fluoropyridin-2-yl)methyl)propanamide (7.28 g, 9.48 mmol) described in Production Example 1-1-4 and formic acid (50 mL) was stirred at room temperature for 15 hours and 15 minutes. The reaction mixture was concentrated under a reduced pressure, an aqueous ammonia solution was added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to give the title compound (5.04 g, yield: 80%).
Reaction SMILES: [F:1][C@:2]1([C:14]([O:16]C)=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[OH-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@:2]([F:1])([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of #166 (272 mg, 1.10 mmol, 1 eq.) dissolved in methanol (2.96 mL) was added an aqueous solution of sodium hydroxide (2.5 M, 0.88 mL) and the reaction was stirred at room temperature for 3.5 hours. The reaction was quenched with 10% aqueous citric acid (5 mL), ethyl acetate (100 mL) was added, and the layers separated. The organic layer was washed with 10% citric acid, water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford #168 as a white solid. (253 mg, 99%). 1H NMR (400 MHz, CDCl3), δ 3.96-3.69 (m, 3H), 3.59 (m, 1H), 2.59-2.33 (m, 2H), 1.51 (s, 9H). LC-MS (Protocol Q1): m/z 232.1 [M−H+], retention time=0.67 minutes. Chiral HPLC retention time: 3.39 min (purity=99%). (Column: Chiralpak AD-H, 4.6 mm×25 cm, mobile phase 5-60% CO2/Methanol, flow rate 3.0 mL/min); Optical rotation: [α]D25 4.8 (c=0.52, MeOH)
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[C:10]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:9]2=[O:32])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[O:20]1[C:13]2=[CH:12][C:11]3[C:10]4([CH2:24][O:23][C:22]5[CH:25]=[C:26]6[C:30](=[CH:31][C:21]4=5)[CH2:29][CH2:28][O:27]6)[C:9](=[O:32])[NH:8][C:16]=3[CH:15]=[C:14]2[O:17][CH2:18][CH2:19]1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3
Yield: 22.5 %

Procedure:
To a solution of 6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one (0.5 g, 1.0 mmol) in trifluoroacetic acid (7 mL) was added triethylsilane (0.47 mL, 3.0 mmol). The reaction mixture was heated at reflux for 3.5 h and concentrated in vacuo. The residue was triturated in methanol to afford 2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one (0.076 g, 23%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 6.61 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 4.66 (ABq, J=36.8, 9.2 Hz, 2H), 4.54-4.44 (m, 2H), 4.24-4.11 (m, 4H), 3.02-2.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 160.8, 160.4, 143.3, 138.7, 135.4, 125.1, 120.9, 119.5, 118.9, 113.0, 99.0, 92.2, 79.7, 72.0, 64.2, 63.7, 57.1, 28.3; MS (ES+) m/z 337.9 (M+1).
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH2:5][CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[N:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][C:4]4[N:10]([CH:1]=[CH:2][N:3]=4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-n1ccnc1CCC2
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine was converted to 5-chloro-N*2*-(5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-yl)-N*4*-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.76 (m, 1H), 7.70 (d, 1H), 7.67 (s, 2H), 7.5 (m, 3H), 7.24 (d, 1H), 3.3 (m, 1H), 2.95 (t, 2H), 2.60 (t, 2H), 2.38 (pent, 2H), 1.19 (d, 6H); 19F NMR (282 MHz, CD3OD) δ −77.4, −114.8 (d); MS (m/e) 527 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]=2)O)=[CH:4][CH:3]=1.Cl.[CH3:31][OH:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]2[O:32][CH3:31])=[CH:4][CH:3]=1
Reactant: CO
Reactant: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Product: COC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 50.9 parts of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol, 320 parts of methanol and 800 parts of a hydrochloric acid solution 1N was stirred first for 3 hours at reflux temperature and then for 56 hours at room temperature. The whole was evaporated till all traces of methanol were removed. The free base was liberated with ammonium hydroxide. The product was extracted with 1040 parts of dichloromethane. The extract was washed with 100 parts of water, dried, filtered and evaporated. The residue was dissolved in 270 parts of N,N-dimethylformamide. The whole was heated to 60° C. 2.5 Parts of a sodium hydride dispersion 50% were added at 80° C. After stirring for 1 hour at 80° C., the mixture was cooled to room temperature. 9 Parts of iodomethane were added dropwise. Upon completion, the whole was stirred and heated for 30 minutes at 40° C. After cooling, the reaction mixture was poured onto 2000 parts of ice-water. The product was extracted twice with 450 parts of methylbenzene. The combined extracts were dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 29.6 parts (57%) of 4-[bis(4-fluorophenyl)methylene]-3-methoxy-1-(phenylmethyl)piperidine as a residue (intermediate 29).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][C@H:13]1[CH2:17][O:16]C(C)(C)[O:14]1>O1CCCC1>[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][C@H:13]([OH:14])[CH2:17][OH:16]
Reactant: CC1(C)OC[C@H](Cn2ccc3c(Br)cccc32)O1
Agent: Cl
Solvent: C1CCOC1
Product: OC[C@@H](O)Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A 2 N aqueous HCl solution (15 ml) was added to a solution of the above mixture (4-bromo-1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indole) in tetrahydrofuran (30 ml), and the mixture was stirred at room temperature for eight hours. The reaction mixture was concentrated, and the residue was then diluted with AcOEt. This organic layer was sequentially washed with water (×2) and a saturated aqueous NaCl solution, and then dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH2Cl2-MeOH) to give (S)-3-(4-bromo-indol-1-yl)-propane-1,2-diol as a colorless solid (2.05 g, 95%).