Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[F:16][C:17]1[CH:18]=[C:19]([C@@H:23]([NH2:25])[CH3:24])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:25][C@H:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH3:24])=[CH:10][CH:11]=1
Reactant: C[C@H](N)c1cccc(F)c1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@@H](C)c1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (547 mg, 2.4 mmol), (S)-1-(3-fluorophenyl)ethanamine (500 mg, 3.6 mmol), K2CO3 (662 mg, 4.8 mmol), and KI (797 mg, 4.8 mmol) in anhydrous CH3CN (15 mL) was stirred at rt under N2. Then the solution was refluxed overnight. The solid was filtered off, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC to afford 3-(4-fluorophenyl)-1-((S)-1-(3-fluorophenyl)ethylamino)hex-5-en-3-ol (350 mg, 44%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].Br[CH2:11][C:12](=O)[C:13]([O:15]CC)=[O:14].C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH3:4][C:3]1([CH3:5])[CH:2]([C:7]([OH:9])=[O:8])[NH:1][C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:6]1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)SC=C(C(=O)O)NC1C(=O)O
Yield: 34.5 %

Procedure:
To a solution of L-penicillamine (298 mg, 2.0 mmol) in water (5 mL) and acetonitrile (5 mL) was added ethyl 3-bromopyruvate (0.25 mL, 390 mg, 2.0 mmol) slowly. To the resulted mixture was added sodium bicarbonate aqueous solution till the pH about 5. Acetonitrile was removed under vacuum and some more water was added. The solution was extracted with methylene chloride. The water phase was separated and freeze-dried under high vacuum. The residue was chromatographed (silica gel, methylene chloride-methanol-acetic acid 100:5:0.3 to 100:10:0.3) to give 150 mg of product (yield 31%). 1HNMR (300 Hz, D3COD) δ (ppm) 6.17 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.79 (s, 1H), 1.48 (s, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.29 (s, 3H). 13CNMR (75 Hz, D3COD) δ (ppm) 173.8, 164.0, 128.0, 102.4, 64.1, 62.2, 41.2, 28.3, 25.2, 14.7 ppm. MS (ESI) m/z 268 (M+Na, 100), 246 (M+1, 5).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10]O)=[N:5]2.Cl.S1C2C=C[N:18]=CC=2C=C1CN>>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10][NH2:18])=[N:5]2
Reactant: OCc1ccc2nccn2n1
Reactant: NCc1cc2cnccc2s1
Agent: Cl
Product: NCc1ccc2nccn2n1

Procedure:
Intermediate 1 was prepared from imidazo[1,2-b]pyridazin-6-ylmethanol (1-4) following the procedures similar to procedure of intermediate D from D-3. MS (m/z): 149 (M+1)+
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:16]1[N:21]2[CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33]I.O>CN(C)C=O>[CH:3]([C@H:16]1[N:21]2[CH2:22][C@@H:23]([O:25][CH3:33])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydride (60% in mineral oil, 14.9 mg) was added into a solution of tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (126.8 mg) in N,N-dimethylformamide (1.5 ml) under ice-cooling. After being stirred for 0.5 hour at the same temperature, methyl iodide was added to the reaction mixture. And this mixture was stirred for 12 hours at room temperature. Then the reaction mixture was poured into water (10 ml). The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:2) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-methoxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (100.5 mg).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:25]=2[N:26]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3sc(C)nc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-methyl-benzothiazol-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 60.9 %

Procedure:
A mixture of 2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.06 ml), water (0.06 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 83) (0.25 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][S:30]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:37][CH2:38]1)(=[O:32])=[O:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(S(C)(=O)=O)CC3)ccc21
Yield: 73.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (42 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 1-methanesulfonyl-piperidin-4-ylamine (60 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 570. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (br, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.74 (br, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 3.92 (br, 1H), 3.63 (s, 3H), 3.58 (m, 2H), 2.87 (s, 3H), 2.82 (m, 2H), 1.83 (m, 2H), and 1.62 (m, 2H), 2 —NH proton signals were not observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[C:8]1([CH2:14][O:15][C:16]([N:18]2[CH:22]([CH2:23][CH2:24][CH:25]=[C:26]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]([O:29][CH3:30])=[O:28])[C:21](=O)[O:20]C2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][C:21](=[O:20])[C@H:22]([CH2:23][CH2:24]/[CH:25]=[C:26](/[C:27]([O:29][CH3:30])=[O:28])\[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH:18][C:16]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)[C@@H](C)N
Reactant: COC(=O)C(=CCCC1C(=O)OCN1C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Product: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ 1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s, 3H); 4.15-4.27 (m,1H); 4.50-4.60 (m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82 (--CHCH3 ; 24.33(--CH2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522MH+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98; H 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:5]=2[CH:4]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>ClC1C=CC=CC=1.CCOC(C)=O>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:4]2[C:5]3[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:6]=3[S:7][C:3]=2[N:2]([CH3:15])[CH3:1])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: COc1cc2sc(N(C)C)cc2cc1F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 116.4 %

Procedure:
A solution of 1.08 g (4.82 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene (Part B) in 15 mL of chlorobenzene was treated with 0.99 g (5.31 mmol) of 4-nitrobenzoyl chloride. The reaction was stirred at room temperature for 17 h and was diluted with 100 mL of EtOAc. The solution was washed sequentially with 2 N aqueous NaOH (2×50 mL), H2O (50 mL) and brine (50 mL), then dried over Na2SO4, and filtered. Evaporation of the solvent in vacuo afforded 2.1 g of a dark solid which was purified by flash chromatography (SiO2; gradient of 10% then 20% then 40% EtOAc in hexanes) to give 0.27 g of starting material and 1.25 g (3.34 mmol; 93% based on consumed starting material) of the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:50])([CH3:49])[O:6][C@H:7]([C@@H:22]([CH3:48])/[CH:23]=[C:24](/[CH3:47])\[CH2:25][C@H:26]([CH3:46])[C@@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:28]([CH3:37])[C@@H:29]([OH:36])[C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:8]([CH3:21])[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])[CH3:3].ClC(Cl)(Cl)[C:53]([N:55]=C=O)=[O:54]>C(Cl)Cl>[NH2:55][C:53]([O:36][C@@H:29]([C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:28]([CH3:37])[C@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C@@H:26]([CH3:46])[CH2:25]/[C:24](/[CH3:47])=[CH:23]\[C@H:22]([CH3:48])[C@@H:7]([O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:49])[CH3:50])[C@@H:8]([CH3:21])[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:54]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of N-[(2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl]-N-methyl-cyclohexaneacetamide (70 mg, 0.096 mmol, 1 eq) in CH2Cl2 (2.0 mL) is treated with trichloroacetyl isocyanate (27.2 g, 0.145 mmol, 1.5 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (2.0 mL). To this solution is added K2CO3 (10 mg) and the mixture is stirred at 23° C. (2 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (10 mL). The organic solution is filtered through Celite and concentrated. Chromatography (SiO2, 0–30% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 94%): HRMS ESI m/z 777.5984 (M+H+, C44H85O5N2Si2 requires 777.5997).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(OC)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-methoxy-phenyl boronic acid (73 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (68 mg, 45%).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]2[CH3:19])=[N:11][CH:12]=1)([OH:6])[CH3:5].C(N(CC)CC)C.[N+:29]([C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl>[N+:29]([C:32]1[S:36][C:35]([S:37]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[N:11]=[CH:12][C:7]([C:4]([OH:6])([CH3:5])[C:3]([F:2])([F:20])[F:21])=[CH:8][N:9]=3)[C@@H:14]([CH3:19])[CH2:15]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
The 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride (95 mg, 0.291 mmol) was dissolved in CH2Cl2 (15 mL) was chilled to 0° C. To this solution was added triethylamine (101 μL, 0.727 mmol) followed by 5-nitrothiophene-2-sulfonyl chloride (66.2 mg, 0.291 mmol, Enamine Building Blocks, Kiev, Ukraine). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated onto silica gel and then purified via column chromatography (24 g silica gel, 0 to 10% MeOH in CH2Cl2) to give racemic 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][S:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:14][C:10]2[CH2:11][S:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:16])([CH3:15])[N:9]=2)=[CH:36][CH:35]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CSCC(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)CSC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution (R)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (910 mg, 3 mmol, Eq: 1.00) and triethylamine (607 mg, 836 μl, 6.00 mmol, Eq: 2) in dichloromethane (30.0 ml) at 23° C. was added 4,4′-dimethoxytrityl chloride (1.12 g, 3.3 mmol, Eq: 1.1) and the mixture was stirred at 23° C. for 2 h. The solution was concentrated in vacuum and directly subjected to silica gel flash chromatography with n-heptane and ethyl acetate to give the (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (1.67 g, 2.76 mmol, 91.9% yield) as an off-white foam. MS (ISP): m/z=605.1 [M+H]+ and 607.2 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: CC(C)CCBr
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-bromo-3-methylbutane using potassium carbonate as a base in DMF at 80° C. Mass: 480.16 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[CH:12]=1.C[Si](Cl)(C)C.[C:31]([Cl:34])(Cl)=[O:32]>ClCCl>[C:22]([O:21][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][C:18](=[O:20])[CH3:19])[C:10]([N:9]([CH3:8])[C:31]([Cl:34])=[O:32])=[O:25])(=[O:24])[CH3:23]
Reactant: CNC(=O)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: O=C(Cl)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)N(C)C(=O)Cl)cc1OC(C)=O

Procedure:
A solution of triethylamine (6.04 g) in dried dichloromethane (20 ml) was added dropwise at room temperature to a solution of N-methyl-3,4-diacetoxybenzamide (15.0 g) and trimethylsilyl chloride (6.49 g) in dried dichloromethane (70 ml). After the mixture was refluxed for 30 minutes a solution (82 ml) of phosgene (42 ml) in dried dichloromethane was added to the mixture at a temperature of from -5° to 5° C. followed by allowing its temperature to gradually rise to room temperature. Excess phsogene and the solvent used were removed by evaporation under reduced pressure to give crude N-(3,4-diacetoxybenzoyl)-N-methylcarbamoyl chloride. The product was dissolved in cold dried dichloromethane (50 ml) and, after removing insoluble substances by filtration, made available for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([NH2:13])=[CH:5][CH:4]=1.[C:14](Cl)(Cl)=[S:15].O>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:6]1[C:7]([C:9]([F:10])([F:11])[F:12])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 6-methoxy-2-(trifluoromethyl)pyridin-3-amine (6.99 g, 36.4 mmol) in tetrahydrofuran (60 mL) and saturated aqueous sodium hydrogen carbonate (60 mL) was added dropwise thiophosgene (2.8 mL, 36.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (8.49 g, 36.3 mmol, quant.) as a pale orange oil.
Reaction SMILES: CC1C=CC(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Cl[C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:12]1([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=[N:11]1
Reactant: O=C(O)c1cnccc1Cl
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1cnccc1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 47 substituting 4-chloronicotinic acid for 2-chloro-6-methylnicotinic acid. MS (ESI):
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]2[N:9]=[C:16]([NH:15][CH:12]([CH3:14])[CH3:13])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(F)c(F)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(F)c(F)c(Cl)cc2[nH]1
Yield: 21 %

Procedure:
5-Chloro-3,4difluoro-1,2-phenylenediamine (11.6 g, crude material), isopropyl isothiocyanate (6.3 g, 62.1 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (28.0 g, 66.2 mmol) and pyridine (250 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a tan solid (3.2 g, 25%); m.p. 175-178° C.; 1H NMR (DMSO-d6) δ: 11.0 (br s, 1H, NH), 7.07 (d, J=5.4 Hz, 1H, Ar—H), 6.96 (br s, 1H, NH), 3.93 (m, 1H, CH), 1.23 (d, J=6.5 Hz, 6H, overlapping CH3). Anal. Calcd. for C10H10F2ClN3-(0.6 C4H8O2): C, 49.89; H, 5.00; N, 14.08. Found: C, 50.29; H, 4.99; N, 14.47.