Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]([N:33]([CH3:43])[CH3:32])=[O:42])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H35N6O3Cl2 [(M+H)+] 609.2142, observed 609.2146.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].CC1(C)C(=O)N(C2C=CC([NH:57][S:58](N)(=[O:60])=[O:59])=C(C)C=2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F>>[CH3:43][C:2]1([CH3:1])[C:3](=[O:42])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:58]([NH2:57])(=[O:60])=[O:59])=[C:31]([CH3:38])[CH:30]=2)[C:5](=[O:28])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[O:17]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Yield: 62 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 30 replacing the compound of Example 1. A white solid is obtained with a yield of 62%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:7][C:6]=2[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH2:31][CH2:30]1
Reactant: FC1(F)CCNCC1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCC(F)(F)CC1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (104 mg, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (43 mg, 0.275 mmol) and potassium carbonate (103 mg, 0.75 mmol) in DMF (2 mL) was heated in microwave at 120° C. for 20 min. The crude was purified by HPLC to give the title compound (20 mg, 18%) as a white solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 2.10-2.23 (m, 4H), 3.10-3.40 (m, 4H), 3.57 (t, 2H), 3.68 (s, 3H), 4.37 (t, 2H), 6.30 (d, 1H), 7.25 (d, 1H), 7.45 (dt, 1H), 7.50 (d, 1H), 7.57-7.62 (m, 1H), 7.72 (d, 1H), 7.74-7.82 (m, 2H), 7.89 (dd, 1H), 10.3 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2. found 459.4 (MH+).
Reaction SMILES: CC[N:3](CC)CC.[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[N:13][CH:14]=1.C(O)(=O)[CH2:20][C:21]([CH2:26]C(O)=O)([C:23](O)=[O:24])O>C1COCC1>[OH:24][CH2:23][C:21]([NH:3][S:15]([C:11]1[CH:12]=[N:13][CH:14]=[C:9]([Br:8])[CH:10]=1)(=[O:17])=[O:16])([CH3:26])[CH3:20]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanole (478 mg, 5 mmol) and Et3N (0.75 mL, 5 mmol) in THF (50 mL) at 0° C. was added portionwise added 5-bromo-pyridine-3-sulfonyl chloride [CAS-No. 65001-21-0] (according to J. Org. Chem. 1989, 54(2), 389) (1.28 g, 5 mmol) and the mixture was stirred at 23° C. for 1 h. The reaction is worked up by neutralization with 5% citric acid, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, filtered and concentrated to give a light brown solid, which was purified by trituration with heptane/diethyl ether gave the title compound as a white solid (1.25 g, 82%). MS (ISP) 309.2 [(M+H)+], 311.1 [(M+2+H)+]; mp 112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[C:44]([F:46])[C:7]([O:8][C:9]2[CH:43]=[CH:42][C:12]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:41])([CH3:40])[C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[C:35]([F:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(C)C>[NH2:37][C:33]1[CH:34]=[C:35]([F:36])[C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]4[CH:42]=[CH:43][C:9]([O:8][C:7]5[C:44]([F:46])=[CH:45][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:10][CH:11]=4)[CH:17]=3)([CH3:40])[CH3:41])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(c1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(c1ccc(Oc2ccc(N)cc2F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc(N)cc3F)cc2)c1
Yield: 81 %

Procedure:
Successively, to a reduction vessel equipped with a thermometer, reflux condenser and stirrer, 115 g (0.184 mol) of 1,3-bis[4-(4-nitro-6-fluorophenoxy)-α, α-dimethylbenzyl]benzene, 250 g of isopropyl alcohol and 4.8 g of 5%-Pd/c having a moisture content of 50% were charged and reacted at 70°~80° C. for 4 hours in a hydrogen atmosphere. After finishing the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 84.2 g (81% yield) of 1,3-bis[4-(4-amino-6-fluorophenoxy)-α, α-dimethylbenzyl]benzene as a light yellow crystal having a melting point of 130.4~132.9.
Reaction SMILES: O(Cl)Cl.[Zr:4].[P:5]([O-:9])([O-:8])([OH:7])=[O:6].[Na+].[Na+]>O>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Zr+4:4].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Zr+4:4].[Zr+4:4]
Reactant: [Zr]
Reactant: O=P([O-])([O-])O
Agent: ClOCl
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]
Temperature: 80 °C
Reaction time: 1 h
Yield: 123.4 %

Procedure:
Zirconium oxychloride (ZrOCl2.8H2O) 36.1 g (0.112 mole) was dissolved in 50 ml of water, and to the resulting solution was added 200 ml of an aqueous solution containing disodium hydrogenphosphate (Na2HPO4) 31.8 g (0.224 mole) to form a white precipitate. The resulting mixture was stirred at 80° C. for one hour, and the white precipitate was sufficiently washed with water by a decantation method, filtered, further washed with water, and dried at 120° C. to obtain zirconium phosphate (Zr(HPO4)2) 30.1 g.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7]O[C:5](=O)[CH:4]=1.[C:16]1(=[O:23])C=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>ClC1C=CC=CC=1Cl.C(Cl)(Cl)Cl.O=[Mn]=O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:20](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[C:19](=[O:22])[CH:18]=[CH:17][C:16]2=[O:23]
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=c1cc(C(F)(F)F)c(C(F)(F)F)co1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21

Procedure:
23.47 g (0.1011 mol) of 4,5-bis-trifluoromethyl-2-oxo-2H-pyran, 54.62 g (0.5053 mol) of 1,4-benzoquinone and 26.30 g (0.3026 mol) of MnO2 in 225 ml of 1,2-dichlorobenzene are heated at 180° C. for 12 hours. The reaction mixture is then diluted with 200 ml of CHCl3 and filtered through Hyflo®. After the chloroform has been removed by distillation, the distillation residue is chromatographed over a column packed with 1300 g of SiO2 (mobile phase: first cyclohexane and then CHCl3 ; 0.3 bar excess pressure). Yield 17.94 g (60.3%), melting point: 91°-94° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:43][C:44]([Cl:48])=[C:45]([NH2:47])[CH:46]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36]>>[Cl:48][C:44]1[S:43][C:42]([S:39](=[O:41])(=[O:40])[NH:38][C:35]([CH3:37])([CH3:36])[CH2:34][OH:33])=[CH:46][C:45]=1[NH:47][C:28]([C:27]1[CH:26]=[N:25][N:18]2[C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:32])([F:31])[F:1])[CH:6]=3)=[N:16][C:17]=12)=[O:29]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[NH2:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[NH:26][C:20]1[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:19]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (1.26 g, 5.0 mmol) and 2-fluoro-4-iodo-phenylamine (1.18 g, 5.0 mmol) in anhydrous THF (25 mL) at −78° C. was added a 1.0M solution of LHMDS in hexanes (10.0 mL, 10.0 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and then stirred for 30 minutes before being quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to give the title compound as a yellow solid (717 mg, 30%). LCMS (method B): RT=5.14 min, [M+H]+=471.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[NH2:48])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:48][C@H:47]([C:49]([OH:51])=[O:50])[CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
3.00 g (6.16 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.43 g (6.16 mmol) N5-(tert-Butoxycarbonyl)-L-ornithine was added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 500 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 30 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.29 g (3.50 mmol, 57% of theory, 89% purity) of the desired product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1>CO.[Pd]>[F:1][C:2]([F:17])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1cccc(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(OC(F)(F)F)c1
Temperature: 15 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 158c (12.0 g, 46.1 mmol) in methanol (100 mL) was added 10% Pd/C (1.0 g), and the reaction mixture was stirred at 15° C. for 16 h under hydrogen atmosphere. See FIG. 4. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford ethyl 3-(3-(trifluoromethoxy)phenyl)propanoate 158d (11.0 g, crude) as a colorless solid.
Reaction SMILES: [CH2:1]([S:8]([CH2:11][CH2:12]Cl)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([S:8]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C1CCNCC1
Reactant: CCCCCCCS(=O)(=O)CCCl
Product: CCCCCCCS(=O)(=O)CCN1CCCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Mix 2-chloroethyl heptyl sulfone (1.1 g, 5 mmol) and piperidine (10 mL). Stir at 60° C. overnight. Add addition piperidine (5 mL) and stir at 60° C. overnight. Cool to room temperature, partition between 5N sodium hydroxide and ethyl ether. Separate the organic phase and extract the aqueous phase with ethyl ether (2×25 mL). Combine the organic phases, dry (MgSO4) and evaporate in vacuo to yield 1.2 g orange oil which crystallizes. Purify by silica gel chromatography (ethyl acetate) to yield 930 mg. Purify again by silica gel chromatography (hexane, then 10% ethyl acetate/hexane, then 50% ethyl acetate/hexane) to yield 360 mg of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][O-].[Na+].IC.O>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: O
Product: CSc1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
6-Chloropyridazine-3-thiol (500 mg, 3.41 mmol) synthesized in Example (118a) was dissolved in methanol (20 mL), and sodium methoxide (203 mg, 3.75 mmol) and iodomethane (234 mL, 3.75 mmol) were added, followed by stirring at 60° C. for 30 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and extraction was carried out twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (515 mg, yield 94%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[Cl-].[Na+]>CN(C)C=O.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4.62 g (17.8 mmol) of commercially available 2,4-dichloro-6,7-dimethoxyquinazoline in 50 ml of dimethylformamide were added 12.4 ml (89.1 mmol) of triethylamine and 3.65 g (19.6 mmol) of N-tert-butoxycarbonylpiperazine, followed by overnight stirring in an atmosphere of argon at room temperature. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried to give 7.15 g (98%) of the desired compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(Cl)C.ClC(OC(Cl)=O)C>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: COc1ccc(C2CCNCC2)cc1

Procedure:
A mixture of 1-benzyl-4-(4-methoxy)phenylpiperidine (XVIII, Step 3, 0.4724 g, 1.7 mmol), dichloroethane (4.4 ml) and 1-chloroethylchloroformate (0.66 ml, 6.1 mmol) is refluxed overnight, then concentrated and the residue refluxed in methanol for 2 hours. After cooling, the solvent is removed and the resulting solids are slurried in dichloromethane. Ether is added and the solids are collected and then partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated to give a residue which is chromatographed on silica gel eluting with methanol/dichloromethane (4/96) containing ammonium hydroxide (0.4%), followed by methanol/dichloromethane (6/94) containing ammonium hydroxide (0.4%). The appropriate fractions are pooled and concentrated to give 4-(4-methoxyphenyl)piperidine (XIX), NMR (CDCl3) 1.66, 1.83, 2.06, 2.58, 2.76, 3.21, 3.79, 6.85 and 7.15 δ.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[C:20]([NH:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1C)=[O:21])([CH3:16])[CH3:15])#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([O:29][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[F:11])[CH:28]=1)=[O:21])([CH3:16])[CH3:15])#[N:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (1.19 g, 7.49 mmol) and 3-(1-cyano-1-methylethyl)-N-(5-hydroxy-2-methylphenyl)benzamide (2.0 g, 7.13 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.47 g, 10.7 mmol), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→0/30), and the obtained solution was concentrated under reduced pressure to give the title compound (2.09 g, 70%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCc3ccc(Cl)cc3)n2)ccc1F
Yield: 56.3 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-(4-chlorophenyl)ethanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 56.3%).
Reaction SMILES: C([N:8]1[CH2:47][CH2:46][C:11]2[N:12]=[C:13]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][N:30]4[S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][C@H:17]3[CH3:25])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.C1COCC1>[OH-].[OH-].[Pd+2].[C].O>[CH3:25][C@H:17]1[N:16]([C:15]2[C:10]3[CH2:9][NH:8][CH2:47][CH2:46][C:11]=3[N:12]=[C:13]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][N:30]4[S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:36])=[O:37])[N:14]=2)[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18]1
Reactant: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)[C@H](C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)[C@H](C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-1-(4-(6-benzyl-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone (0.35 g, 0.539 mmol), acetic acid (0.154 mL, 2.70 mmol), THF (9 mL) and H2O (3 mL) was degassed via vacuum and recharged with nitrogen gas (2×). Then 20 mol % Pd(OH)2/carbon (0.114 g, 0.162 mmol) was added and the mixture was degassed via vacuum and placed under an atmosphere of hydrogen. The mixture was stirred at rt under H2 atmosphere via balloon for 2 h and then filtered. The solution was then diluted with EtOAc and washed with sat aq NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone, which was used without the need for further purification. MS (ESI+) m/z 559.3 (M+H)+.