Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.C([O-])(=O)C.[Na+].Cl.C(OC(=O)[C@H](CS)N)C>C(O)C>[OH:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][CH2:10]2)[CH2:19]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(=O)[O-]
Agent: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCO
Product: C[C@@]12CCC[C@H]1[C@@H]1CC=C3C[C@@H](O)CC[C@]3(C)[C@H]1CC2

Procedure:
Following the procedure described by Djerassi (C. Djerassi, N. Crossley and M. A. Kielczewski, J. Org. Chem. 27, 1112, 1962), dehydroepiandrosterone (2.88 g, 10 mmol) is dissolved in anhydrous ethanol, sodium acetate is added followed by L-cysteine ethyl ester hydrochloride (18g, 100 mmol) and the mixture is heated overnight under an argon atmosphere. The reaction mixture is then evaporated under vacuum. Methylene chloride is added to precipitate excess of L-cysteine ethyl ester hydrochloride. The solution is then filtered and the filtrate is washed twice with water, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue is triturated with ethanol to give crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:6].[H-].[Na+].CO>CN(C=O)C.C1COCC1.C(Cl)(Cl)Cl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: O=C(NCCCl)Nc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
1-(2-Chloro-ethyl)-3-naphthalen-2-yl-urea (I-79a: 750 mg, 3.01 mmol) in dry DMF (10 mL) was added to a stirred solution of sodium hydride (150 mg, 3.1 mmol) in THF (10 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC (5% MeOH in chloroform, double run). The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 600 mg (94% yield) of 1-naphthalen-2-yl-imidazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of tert-Butyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (80 mg, 0.14 mmol) and TFA (3 mL) in dichloromethane (3 mL) was stirred for 2 h at room temperature. The mixture was concentrated and then triturated with MeOH (2 mL) to give the product 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoic acid (28 mg, 39%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.71 (s, 1H), 10.02 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 8.12 (d, 1H, J=7.5 Hz), 7.97-7.93 (m, 2H), 7.76-7.71 (m, 3H), 7.44 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.4 Hz), 4.05 (s, 3H), 3.88 (s, 3H). LC-MS: [M+H]+, 510.9, tR=1.505 min, HPLC: 97.21% at 214 nm, 99.12% at 254 nm, tR=6.006 min.
Reaction SMILES: [CH2:1]([CH:8]([C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>CC#N>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:10][C:9](=[O:11])[CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NOCc1ccccc1)C(Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Intermediate (12a) (0.5 g, 1.7 mmol) was added to N-hydroxysuccinimide (290 mg, 2.6 mmol) and EDC (320 mg, 1.7 mmol) and dissolved in MeCN (6 mL). The mixture was stirred overnight at room temperature and then partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to provide intermediate (12b) as a foam (0.8 g, 2 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:29])[C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[NH:25][C:21]=3[CH:20]=2)=[O:18])[CH2:12][CH2:11]1.[BH4-].[Na+].Cl>CO>[OH:18][CH:17]([C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[NH:25][C:21]=2[CH:20]=1)[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:11][CH2:12]1)[CH3:29]
Reactant: COc1ccccc1N1CCN(C(C)C(=O)c2ccc3[nH]c(=O)[nH]c3c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1N1CCN(C(C)C(O)c2ccc3[nH]c(=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
The 5-(2-(4-(2-methoxyphenyl)piperazin-1-yl)propanoyl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.67 g, 4 mmol) was dissolved in 50 ml of methanol solution, and sodium borohydride (0.15 g, 8.4 mmol) was added in proportions, mixed and stirred at room temperature for 3 hours. Working up according to general procedure B gave 0.57 g of (1RS, 2SR)-5-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2(3H)-one (IV-3) hydrochloride having a melting point of 221 to 223° C., with a yield of 34.0%; and 0.50 g of (1RS,2RS)-5-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2(3H)-one (IV-4) hydrochloride having a melting point of 242 to 244° C., with a yield of 29.8%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:6]([NH2:8])[NH2:7])[CH3:2].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH2:9][CH2:10][C:11]([NH2:12])=[N:8][C:6]=1[NH2:7])[CH3:2]
Reactant: CCOC(=O)C(CCC#N)=C(N)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(N)N=C(N)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-(2-cyanoethyl) 3,3-diaminopropenoic acid ethyl ester described in Preparation Example A-12 (0.55 g, 3 mmol) in tetrahydrofuran (7 mL) was added dropwise to a suspension of sodium hydride (208 mg, 5.2 mmol, 60% in oil) in tetrahydrofuran (7 mL), and the solution was stirred for 19 hours 20 minutes under reflux. After the reaction was completed, the reaction solution was poured into an ice water, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated to obtain the title compound as a crude product (0.188 g, 1 mmol, 34%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[Li]CCCC.CCCCCC.B(OC)(OC)OC.[CH3:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](OS(C(F)(F)F)(=O)=O)=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1>C1COCC1.CCOC(C)=O.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>[O:4]1[CH:5]=[CH:6][C:2]([C:30]2[C:29]3[C:34](=[CH:35][C:26]([CH3:25])=[CH:27][CH:28]=3)[O:33][C:32](=[O:36])[CH:31]=2)=[CH:3]1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc2c1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromofuran (1.9 g, 12.7 mmol) in dry ET2O (30 mL) at -70° C. was added BuLi in hexane (1.9M, 6.7 mL, 12.7 mmol) and the resulting mixture was stirred for 20 min.. Trimethyl borate (Aldrich) (1.4 mL, 12.7 mmol) was added dropwise and the mixture stirred for 20 min.. A solution of the triflate from Step 4 in THF: H2O (24 mL: 6 mL) containing (Ph3P)4Pd (1.1 g, 0.97 mmol) was added and the reaction was heated to reflux for 16 h. The reaction mixture was cooled to r.t. and EtOAc was added and the organic phase washed with H2O (3×), brine, dried over MgSO4 and evaporated to give a white solid. A swish in EtOAc gave after filtration 1.8 g (82%) of the title compound.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH:33](O)[CH2:34][CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH:34]([CH3:35])[CH2:33][NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH:34]([CH3:35])[CH2:33][NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCC(N)O
Solvent: CCO
Product: CC(CN)OB(c1ccccc1)C(OC(B(OC(C)CN)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (40 mg) was obtained by allowing 41 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 18 mg of 1-aminopropanol to act in 1 mL of ethanol.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>CO.C(Cl)(Cl)Cl>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: CCCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-propylphenyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHCl3 a brown solid (76.1 mg) which was further purified using preparative HPLC to give the pure sulfonamide as a tan colored oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:6][CH:7]=1)[CH2:12][CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CCC(=O)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CCC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:18]([O:22][N:23]1N=NC2C=CC=C[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[CH3:18][O:22][N:23]([CH3:24])[C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
2-tert-Butoxycarbonylamino-butyric acid (500 mg, 2.46 mmol), HBTU (1.03 g, 2.71 mmol) and DIPEA (1.22 mL, 7.38 mmol) were dissolved in DMF (10 mL) and stirred for 30 min. N,O-dimethylhydroxylamine hydrochloride (360 mg, 3.69 mmol) was added and the reaction mixture was stirred for 1 h. The solvents were removed in vacuo and the residue was purified by column chromatography to give the title compound (380 mg, 63%) as a cream oil. LCMS (ES+): 269.2 [MNa]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([F:19])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-])=O.[NH4+].[Cl-]>[Fe]>[NH2:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[S:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH:20][C:21](=[O:23])[CH3:22])=[CH:5][C:6]=1[F:19]
Reactant: CC(=O)Nc1cc(F)c(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)Nc1cc(F)c(Sc2ccc(C)cc2N)c(F)c1

Procedure:
The product from Example 40a was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][C:28]4([CH2:27][O:26][CH3:25])[CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC1(CN)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC1(CNC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-(methoxymethyl)cyclopropyl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36-0.44 (m, 2 H) 0.52-0.60 (m, 2 H) 2.43 (s, 3 H) 3.22-3.28 (m, 5 H) 3.35 (s, 2 H) 7.66 (d, J=7.83 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.08-8.26 (m, 1 H) 8.42 (d, J=6.57 Hz, 2 H) 8.64 (t, J=5.56 Hz, 1 H) 8.88-8.94 (m, 1 H) 12.96-13.46 (m, 1 H). MS m/z [M+H]+ 418.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
The solution of tert-butyl 4-(3-(2-methoxy-2-oxoethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (330 mg, 1.0 mmol) and Pd/C (30 mg) in methanol (10 mL) was stirred under H2 at room temperature for 12 h. Then, the reaction mixture was filtered and evaporated under reduced pressure to get desired product for the next step without further purification. LC-MS: m/z (M+H)=334.4
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[ClH:8].Cl.[NH2:10][C:11]1[CH:12]=[C:13]([C:19](=[O:40])[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH2:24][CH2:23]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[ClH:8].[CH2:38]([O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:1](=[O:3])[CH3:2])[CH:12]=2)=[O:40])[CH2:23][CH2:24]1)[CH3:39]
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NC(C)=O)c2)CC1
Reaction time: 12 h

Procedure:
Acetic acid anhydride (0.132 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (276 mg). The free base compound (270 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless crystals having a melting point of 127 to 129° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([O:18][CH2:19][CH2:20][OH:21])([CH3:17])[CH3:16].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:21][CH2:20][CH2:19][O:18][CH:15]([CH3:17])[CH3:16])[N:10]=1
Reactant: CC(C)OCCO
Reactant: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a mixture of 2,6-dichloro-5-cyclopropylnicotinamide (450 mg, 1.95 mmol) and 2-isopropoxyethanol (223 mg, 2.14 mmol) in DMF (30 mL) was added and NaH (86 mg, 2.14 mmol) in portions at 0° C. The mixture was stirred at r.t overnight, quenched by water, extracted by EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinamide (180 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.08 (s, 1H), 7.93 (s, 1H), 5.85 (s, 1H), 4.60 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 2.05 (m, 1H), 1.18 (d, J=6.0, 6H), 1.02 (m, 2H), 0.71 (m, 2H).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19].[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O>[N:20]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19])=[N+:21]=[N-:22]
Reactant: O=C1Nc2cc(-c3ccccc3)ccc2CCC1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2ccc(-c3ccccc3)cc2NC1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture comprising 0.93 g (3.42 mmol) of 3-chloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one obtained in the Synthesis Example A-5, 0.27 g (4.18 mmol) of sodium azide and 15 ml of dimethyl sulfoxide was stirred at 80° C. for 3 hours. After further adding 0.05 g of sodium azide and stirring for 30 minutes, the reaction mixture was added to ice water. The crystals were collected by filtration and dried under reduced pressure to thereby give 0.77 g of the title compound. Yield 81%.
Reaction SMILES: Cl[C:2]1C(F)=C(C(F)=C[CH:9]=1)C=O.[Br:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[C:16]([Cl:22])=[CH:15][CH:14]=1>>[Br:12][C:13]1[C:18]([C:19](=[O:20])[CH:2]=[CH2:9])=[C:17]([F:21])[C:16]([Cl:22])=[CH:15][CH:14]=1
Reactant: O=Cc1c(Br)ccc(Cl)c1F
Reactant: O=Cc1c(F)ccc(Cl)c1F
Product: C=CC(=O)c1c(Br)ccc(Cl)c1F

Procedure:
1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 6-bromo-3-chloro-2-fluorobenzaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz, 1H), 6.07 (d, J=17.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:15][CH:14]([O:16][CH3:17])[CH:13]([O:18][CH3:19])[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:19][O:18][CH:13]1[CH:14]([O:16][CH3:17])[CH2:15][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12]1
Reactant: COC1CC2(Cc3ccc(Br)cc3C2=O)CC1OC
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC1CC2(Cc3ccc(-c4cccc(C#N)c4)cc3C2=O)CC1OC
Temperature: 110 °C
Yield: 97 %

Procedure:
In a microwave vial was placed 6′-bromo-3,4-dimethoxyspiro[cyclopentane-1,2′-inden]-1′(3′H)-one 1st isomer (23 mg, 0.071 mmol), 3-cyanobenzeneboronic acid (14 mg, 0.095 mmol), PdCl2(PPh3)2 (5 mg, 0.007 mmol) and cesium carbonate (58 mg, 0.178 mmol). This solid mixture was dissolved in a Dioxane/water mixture (1.0 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. The vessel was placed in the microwave and heated to 110° C. for 30 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (2 mL) and water (2 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (2 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(3,4-dimethoxy-1′-oxo-1′,3′-dihydrospiro[cyclopentane-1,2′-indene]-6′-yl)benzonitrile 2nd isomer (24 mg, 0.069 mmol, 97% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]2[C:4](=[C:5]([O:19]CC=CC)[CH:6]=[CH:7][C:8]2([CH3:18])C)[C:3]1=[O:24].[CH2:25]1[C:34]2C(=CC=CC=2)C[CH2:27][CH2:26]1>>[CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([OH:19])[C:6]([CH:26]([CH3:27])[CH:25]=[CH2:34])=[CH:7][C:8]=2[CH3:18])[C:3]1=[O:24]
Reactant: CC=CCOC1=C2C(=O)C(C)C(c3ccccc3)C2C(C)(C)C=C1
Reactant: c1ccc2c(c1)CCCC2
Product: C=CC(C)c1cc(C)c2c(c1O)C(=O)C(C)C2c1ccccc1

Procedure:
11 Grams of 2,3-dihydro-2,4-dimethyl-3-phenyl-4-methyl-7-crotyloxy-1H-inden-1-one was added to 55 ml of tetrahydronaphthalene and the mixture was heated and refluxed for 6 hours with stirring condition. After the reaction was completed, the reaction mixture was concentrated by removal of the solvent, and the residue thus obtained was purified by means of a silica gel column chromatography. 11.2 Grams of 2,3-dihydro-2,4-dimethyl-3-phenyl-6-(1-buten-3-yl)-7-hydroxy-1H-inden-1-one was obtained as cis-trans mixture. Yellow oily substance.