Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 34% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-10.15 (c=0.47, methanol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[C:4]([Cl:13])=[CH:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cc(C=O)ccc21
Solvent: CC#N
Product: Cn1cc(Cl)c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-Methylindol-5-carbaldehyde (400 mg, 2.5 mmol) was dissolved in dry acetonitrile (10 mL) and treated with N-chlorosuccinimide (400 mg, 3.02 mmol), whereupon the solution turned red. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed in vacuum and the residue was purified by column chromatography (silica gel 60). Yield: 300 mg (1.55 mmol, 62%); colorless solid of mp 109° C.; Rf=0.27 (ethyl acetate/n-hexane 1:4); νmax (ATR)/cm−1 3103, 2845, 2751, 1680, 1602, 1454, 1414, 1362, 1343, 1274, 1238, 1196, 1160, 1134, 1111, 981, 894, 796, 717; 1H NMR (300 MHz, CDCl3) δ 3.75 (3H, s), 7.07 (1H, s), 7.32 (1H, d, J=8.6 Hz), 7.76 (1H, dd, J=8.6 Hz, J=1.5 Hz), 8.07 (1H, d, J=1.5 Hz), 10.01 (1H, s); 13C NMR (75.5 MHz, CDCl3) δ 32.9, 106.3, 109.9, 122.0, 123.3, 125.2, 126.9, 129.2, 138.5, 191.7; m/z (EI) 193 (100) [M+], 164 (57), 128 (43), 101 (48), 87 (28).
Reaction SMILES: Br.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][C:18]4([C:24]5[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=5)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1.C(N(CC)CC)C.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45]>ClCCl>[CH3:42][C:43]([CH3:48])([CH3:47])[C:44]([N:21]1[CH2:20][CH2:19][C:18]([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)([CH2:17][CH2:16][N:15]2[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH2:9][CH:8]([N:7]2[C:6]4[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=4[N:4]=[C:3]2[CH3:2])[CH2:14]3)[CH2:23][CH2:22]1)=[O:45]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(O)c2)CCNCC1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(O)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A mixture of 3-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol hydrobromide (0.22 g, 0.42 mmol), triethylamine (0.117 mL, 0.84 mmol) and trimethylacetyl chloride (0.057 mL, 0.462 mmol) in dichloromethane (2 mL) was stirred at rt for 3 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 3-(1-(2,2-dimethyl propanoyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol as a white solid (0.070 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.05-7.15 (m, 3H), 6.77 (m, 1H), 6.73 (s, 1H), 6.59 (m, 1H), 4.51 (m, 1H), 3.74 (m, 2H), 3.24 (m, 4H), 2.47 (s, 3H), 2.36 (m, 2H), 1.97 (m, 2H), 1.86 (m, 4H), 1.75 (m, 6H), 1.58 (m, 2H), 1.15 (s, 9H). HRMS C33H44N4O2 m/z 529.3543 (M+H)Cal., 529-3542 (M+H)Obs..
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[C:21]([O:35][CH2:36][CH2:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH:20]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:45]([N:52]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:53]1[CH:58]=[N:57][CH:56]=[C:55](B2OC(C)(C)C(C)(C)O2)[N:54]=1)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>>[C:71]([O:70][C:68]([N:52]([C:45]([O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:46])[C:53]1[N:54]=[C:55]([C:2]2[N:3]=[C:4]([N:11]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][O:33][CH2:34]5)[CH2:27][CH2:26]4)=[C:21]([O:35][CH2:36][CH2:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH:20]=3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:56]=[N:57][CH:58]=1)=[O:69])([CH3:72])([CH3:73])[CH3:74]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1)c1nc(Br)cn2ccnc12
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)c(OCCOC4CCCCO4)c3)n2)n1

Procedure:
tert-Butyl (6-bromoimidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVI was reacted with XV according to the methods of CHEMISTRY B as described in Example 2 to provide the desired compound tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVII.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)(=[O:4])=[O:3].O.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:10]1[CH:9]=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: COc1cccc(S(C)(=O)=O)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(S(C)(=O)=O)c1
Reaction time: 15 h
Yield: 45 %

Procedure:
1-Methanesulfonyl-3-methoxy benzene was dissolved in 90 mL glacial acetic acid. 100 mL water was added. A solution of bromine (4.79 g, 30 mmol) in 10 mL acetic acid was added dropwise at 10° C. The stirring was continued at rt for 15 h. The pH of the mixture was adjusted to pH 8 with aqueous NaOH solution, and extracted with EtOAc (3×200 mL) and dried over Na2SO4. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 20% EtOAc in hexanes as an eluent) to give 1-bromo-2-methanesulfonyl-4-methoxy benzene (2.4 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[NH4+].[Cl-]>COCCOC.CO.[Pd]>[NH2:17][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COCCOc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: COCCOC
Product: COCCOc1cc(C(N)=O)c(N)cc1OC
Reaction time: 12 h

Procedure:
A mixture of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide (4.5 g, contains some NH4Cl) and 10% Pd/C (ca. 0.5 g) in DME (200 mL) and MeOH (200 mL) was hydrogenated under a balloon of H2 at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to give 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzamide as an off white solid (2.8 g, 11.6 mmol). HPLC retention time 2.80 mins.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23](SC)=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6].CC(C)([O-])C.[K+].P(=O)(O)(O)O>C(O)C.O>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23]([NH:3][C:2]#[N:1])=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: N#CN
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC#N
Reaction time: 2.5 h
Yield: 50.6 %

Procedure:
Cyanamide (0.2 g, 4.8 mmols) is added to a solution of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (1.5 g, 3.9 mmols) and potassium tert-butoxide (0.5 g, 4.3 mmols) in ethanol (25 mL) and the mixture is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is allowed to cool, and is then poured into water (200 mL), acidified with phosphoric acid, and stirred. After half an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyanamide (0.7 g), mp 257°-259° C. (dec).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:54])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:38]=[C:39]([CH2:45][O:46]C3CCCCO3)[S:40][C:41]=2[CH2:42][CH2:43][CH3:44])[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:54])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:38]=[C:39]([CH2:45][OH:46])[S:40][C:41]=4[CH2:42][CH2:43][CH3:44])[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCc1sc(COC2CCCCO2)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1sc(CO)nc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (79 mg) (Example J6) and 3-oxo-3-{3-[-5-propyl-2-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl}-propionic acid tert-butyl ester (138 mg) (Example K41) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as yellow solid (45 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH:23]=[CH:22][N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I.[Cu]I>[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[C:3]1=[O:18]
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: FC(F)(F)Oc1cccc(-c2ccnc(I)c2)c1
Agent: I[Cu]I
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Copper Iodide (104.92 mg, 0.5500 mmol), followed by PdCl2(Ph3P)2 (193.34 mg, 0.2800 mmol) was added portionwise to a solution of the tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (2.78 g, 11.02 mmol) (which may be prepared as described in Description 8), 2-iodo-4-[3-(trifluoromethoxy)-phenyl]pyridine (6.03 g, 16.53 mmol) (which may be prepared as described in Description 9) and Et2NH (5.7 mL, 55.09 mmol) in THF (60 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. Additional PdCl2(Ph3P)2 (1.25 mol %) and CuI (2.5 mol %) catalyst was added. The reaction was left to stir for 3 days. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with 100 g SNAP cartridge, eluting with 0 to 100% EtOAc in i-hexane. Clean fractions were collected and the solvent evaporated to afford a yellow oil. The remaining fractions were collected and re-columned using a SP4, 100 g SNAP cartridge, 0 to 10% MeOH/EtOAc and the product was collected and combined with the clean material from the first column to afford the tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (D10) (5.38 g, 10.991 mmol, 99.8% yield) as a yellow oil containing some Ph3P residues;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([OH:29])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:29][C:24]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[N:23]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Reactant: Cc1cc(C)nc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2nc(C)cc(C)n2)c(Cl)c1=O
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (Intermediate 79 step 1, 15.4 g, 48 mmol) in N,N-dimethylformamide (150 mL) was treated with 4,6-dimethyl-pyrimidin-2-ol (5.98 g, 48 mmol) and potassium carbonate (8 g, 58 mmol). The reaction was heated at reflux for 12 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography (5/1 petroleum ether/ethyl acetat) afforded 2-[5-chloro-4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (7.47 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)OC
Yield: 109.1 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.3 mmol) in acetone (20 mL) and potassium carbonate (2.6 g, 19 mmol) was added 4-chlorobenzyl chloride (1.1 g, 6.6 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-chloro-benzyloxy)-phthalic acid dimethyl ester (2.3 g, 110% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[CH3:20][S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)[C:3]([CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:37][CH2:38]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:18])=[O:19]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
An orange suspension of methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.068 g, 2.126 mmol) and 4-(1-pyrrolidinyl)piperidine (0.492 g, 3.19 mmol) in acetonitrile (14.17 ml) was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was absorbed onto florisil and was purified via column chromatography (ISCO, 12 g silica, 5-10% methanol/dichloromethane) to give methyl 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.14 g, 88% yield). MS (m/z) 576.2 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:26][NH:25][N:24]=2)=[CH:19][CH:18]=1>C(OCC)C>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:25]2[CH2:26][CH:27]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[N:24]2)=[O:15])=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc(N=C=O)cc1
Reactant: N#CCCCC1CNN=C1c1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(C)OC(=O)c1ccc(NC(=O)N2CC(CCCC#N)C(c3ccc(Cl)cc3)=N2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
51.5 g of the above-prepared 4-isopropoxycarbonylphenyl isocyanate were added to a solution of 61.9 g of 3-(4-chlorophenyl)-4-(3-cyanopropyl)-2-pyrazoline in 450 ml of diethyl ether at room temperature. After stirring for 30 minutes at room temperature, 500 ml of petroleum ether (40-60) were added, after which the reaction mixture was stirred at room temperature for another hour. The crystalline precipitate was sucked off, washed with petroleum ether (40-60) and dried in air. 95.0 g Of 1-(4-isopropoxycarbonylphenylcarbamoyl)-3-(4-chlorophenyl)-4-(3-cyanopropyl)-2-pyrazoline were obtained. After stirring 10 g of the resulting product with 100 ml of diethyl ether, a product was obtained having a melting point of 109°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cccc1Cl
Reactant: O=S(Cl)Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cccc1Cl
Temperature: 85 °C
Reaction time: 26 h

Procedure:
A stirred suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide (14.5 g, 47.8 mmol) in thionyl chloride (130 mL) was heated at 85° C. for 20 hours and then at 90° C. for 26 hours under argon. After cooling to room temperature, the volatiles were removed under reduced pressure, azeotroped with toluene (×3) to afford the title compound as a yellow solid (15.7 g, quantitative). LCMS (Method D): RT=4.16 min, m/z: 321 [M+H+].
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:22])[CH2:18][S:19]([CH3:21])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])[OH:32].[Na+]>CS(C)=O>[CH2:1]([N:8]([C@@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:22])[CH:18]([OH:32])[S:19][CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(O)C(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
309.6 mg (0.763 mmol) of (3S)-3-(N,N-dibenzyl)amino-1-methylsulfinyl-2-oxo-4-phenylbutane was dissolved in 6 ml of dimethylsulfoxide, and 1.5 ml of 2N hydrochloric acid was added thereto and stirred at room temperature for 16 hours. While being cooled in an ice bath, this was neutralized with 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, and then subjected to phase separation with 20 ml of ethyl acetate and 10 ml of water. The resulting aqueous layer was extracted twice with 10 ml of ethyl acetate. The organic layers were combined, then washed with 20 ml of water and 20 ml of a saturated saline solution in that order, and thereafter dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 371.5 mg of a crude product of the above-entitled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[CH:32][C:25]=12.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([C:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[N:31]=[CH:32][C:25]=34)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3cnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Cl)cc21
Yield: 86.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-chloro-thiochromane-7-carboxylic acid (150 mg), 4-amino-1-triphenylmethylpyrazolo[3,4-b]pyridine (163 mg) and 2-chloro-1-methylpyridinium iodide (133 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-chloro-N-(1-triphenylmethylpyrazolo[3,4-b]pyridin-4-yl)thiochromane-7-carboxamide (262 mg) was obtained as a pale yellow amorphous solid.