Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([F:26])[CH:22]=[CH:21][CH:20]=3)[C:14]([OH:27])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([F:26])[C:24]=4[CH:25]=[C:17]3[C:15]=2[N:16]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: Cc1cccc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2C(c2ccccc2)Oc2ccc(Cl)nc2-1
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
A solution of dibromotoluene (382 mg, 1.527 mmol, prepared using similar method described for Example 1) in DMF (2 mL) was added slowly to a mixture of compound 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (200 mg, 0.763 mmol) and Cs2CO3 (746 mg, 2.289 mmol) in DMF (10 mL) at 100° C. After 10 min, the mixture was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (25 mL×3). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=50:1) to provide 2-chloro-11-fluoro-6-phenyl-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (187 mg, yield: 70.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.43 (s, 1H), 7.23˜7.35 (m, 3H), 7.18 (s, 1H), 7.10 (s, 1H), 7.03˜7.08 (m, 4H), 6.79 (m, 1H), 6.65 (d, J=8.4 Hz, 1H). MS (M+H)+: 351/353.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH2:21][CH3:22])=[O:13])[CH3:22]
Reactant: CCc1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1CC
Yield: 33.6 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-ethylaniline (1.40 g, 11.6 mmol) in 12 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 1.0 g of the title compound, mp 255°-256° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:19].[H-].[Na+]>C1COCC1>[N:14]([C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[O:17][CH3:19])=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
To a stirred mixture of 146A (320 mg, 1.32 mmol) and iodomethane (0.25 mL, 3.96 mmol) in 4 mL of dry THF at room temperature under nitrogen was added 95% NaH (40.0 mg. 1.58 mmol). This mixture was stirred at room temperature for 15 h and then quenched by addition of 30 mL of water. The aqueous solution was extracted with EtOAc (2×40 mL). The combined EtOAc extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to give 310 mg (Yield: 92%) of 247A. It had an analytical HPLC retention time=2.86 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++Na=279.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C@@H:19]([CH:35]([CH3:37])[CH3:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)[C@@H:10]([OH:17])[CH2:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].N1C=CN=C1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C@@H:19]([CH:35]([CH3:37])[CH3:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)[C@@H:10]([O:17][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)O)C(C)C)ccc1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reaction time: 16 h

Procedure:
4.45 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (crude) are stirred in 45 ml of dimethylformamide with 2.36 g of tert-butyldimethylsilyl chloride and 2.03 g of imidazole for 6 days at room temperature. The mixture is concentrated by evaporation and the residue is partitioned between 10% citric acid solution and ethyl acetate. The organic phase is concentrated and stirred in 20 ml of tetrahydrofuran, 8 ml of water and 20 ml of acetic acid at room temperature for 16 hours. After concentration by evaporation, ice/water is added to the residue and the mixture is then extracted with ethyl acetate. The title compound is obtained from the organic phase after FC (260 g of silica gel, ethyl acetate/hexane=1:1): Rf (ethyl acetate/hexane=1:1)=0.32.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([OH:11])(=[S:10])[CH3:9].[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34]Cl)[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][S:10][C:8](=[O:11])[CH3:9])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(O)=S
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to 80 ml of dimethylformamide under an atmosphere of nitrogen gas, and then 10 ml of a dimethylformamide solution containing 0.81 ml of thioacetic acid was added to the resulting mixture. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, 30 ml of a dimethylformamide solution containing 3.79 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was then added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and water. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 5.04 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH3:12][CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([C:13]([CH3:12])([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)C(C)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C(=O)OC)C(C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl methylmalonate (160 μl, 1.2 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), showing that the isolation yield of the product was 94%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=95:5, flow rate 0.5 m/min, detection by 210 nm), resulting to 97% ee.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23]CC)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using (R)-ethyl 3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (EXAMPLE 33 Step 1) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinate.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])(=[O:3])[CH3:2].C(O)(=O)C.OO.[S:25]([O-:28])(O)=[O:26].[Na+]>O>[C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:25](=[O:28])(=[O:26])[CH2:16][C:8]([CH3:15])([CH3:9])[C:7]2=[O:17])(=[O:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Yield: 97 %

Procedure:
A 100-ml round-bottomed flask was charged with 1.18 g (4.50 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one, 2 ml of acetic acid and 1.12 g (9.88 mmol) of a 30 wt % hydrogen peroxide aqueous solution, and the mixture was allowed to react at 80° C. for 2 and half hours. The reaction mixture was diluted with about 30 ml of water, and a sodium hydrogensulfite aqueous solution was added to decompose excess peroxide. Then, the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1.28 g (yield 97%) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CCCCCI
Reactant: Cc1cc(=O)c(O)c(CO)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1c(CO)oc(C)cc1=O
Yield: 60 %

Procedure:
To a solution of 2.00 g (0.0304 mole) of potassium hydroxide in 33 ml of ethanol and 5 ml of water was added 4.75 g (0.0304 mole) of 2-hydroxymethyl-3-hydroxy-6-methyl-4-pyrone, and the resulting mixture heated to 50°. A 7.8 g (0.029 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 5.4 g (60%) of oily product, 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J = 7 Hz), 2.26 (3H, s); 4.61 (2H, m); 6.17 (1H, s).
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=O)[NH:21][C:20]=2[CH:31]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]([Cl:12])[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH:22]=[N:21][C:20]=2[CH:31]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
N,N-dimethylaniline (5.1 ml, 40 mmol) and phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (2.45 g, 10 mmol) in dry toluene (20 ml). The mixture was shaken at 95° C. for 2 h. The temperature was then decreased and the excess N,N-dimethylaniline and phosphorus oxychloride were removed at reduced pressure using an oil pump. The remaining oil was dissolved in dioxane (20 ml) and aqueous Na2CO3-solution (10 ml, 2 M) was added. The two-phase mixture was shaken at 80° C. for 30 min. The temperature was then decreased and ether was added to the reaction mixture. The ethereal phase was washed with saturated aqueous NaCl-solution, dried (Na2SO4) and finally concentrated at reduced pressure. The obtained oil crystallized upon standing at room temperature. Recrystallization (heptane-ether) gave 1.8 g (69%) of the title compound (160FE64). 1H NMR (CDCl3) δ 7.61 (dd, 1H, J=1.4, 7.8 Hz), 7.31 (dt, 1H, J=1.5, 8.0 Hz), 7.15 (d, 1H, J=2.5 Hz), 7.02 (m 2H), 6.66 (dd, 1H, J=1.0, 7.8 Hz), 6.58 (d, 1H, J=8.4 Hz), 4.94 (bs, 1H). 13C NMR (CDCl3) δ 157.2, 152.4, 140.3, 138.9, 134.0, 131.9, 129.7, 128.5, 128.0, 127.0, 123.5, 121.0, 119.8.
Reaction SMILES: C1COCC1.[C:6]([C:8]1[CH:9]=[C:10]([CH2:13][O:14][CH3:15])[O:11][CH:12]=1)#[CH:7].I[C:17]1[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=1>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.[Cu]I.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:6]#[C:7][C:17]2[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: C#Cc1coc(COC)c1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2coc(COC)c2)cc1
Yield: 82.9 %

Procedure:
PdCl2(PPh3)2 (70 mg), CuI (38 mg) and TEA (1.5 mL) were added to a THF (7.0 mL) solution of 4-ethynyl-2-(methoxymethyl)furan (0.24 g) as obtained in Example 18-(3) and (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 0.51 g), and the mixture was stirred for 5.5 hours at room temperature in a nitrogen atmosphere. Ethyl acetate (30 mL), OH type silica gel (1.9 g), cellpure (0.95 g) and activated carbon (50 mg) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with ethyl acetate/hexane=75/25→100/0, followed by gradient elution with chloroform/acetone=100/0→70/30) to obtain (2S)-2-[(4-{[5-(methoxymethyl)furan-3-yl]ethynyl}benzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.43 g, 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: CC(C)N1CCCNCC1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCN(C(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (209 mg, 1.21 mmol) in dichloromethane (4.00 ml) was added to a stirred solution of 1-propan-2-yl-1,4-diazepane (172 mg, 1.21 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.523 ml, 3.02 mmol) in dichloromethane (4.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (267 mg, 79%) as a cream oil which crystallised on standing. This was used directly with no further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C1C[O:28][CH2:27]C1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:27]=[O:28])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-tert-butyloxycarbonylaminothiazole (88.0 g, 439 mmol) in THF (1760 ml) was added dropwise a 1.59M solution of n-butyllithium in hexane (729 ml, 1159 mmol) over 20 minutes at −78° C., and the mixture was warmed to −10° C. over 1 hour. The mixture was cooled again to −78° C. and thereto was added DMF (102 ml, 0.132 mmol) in one portion. The acetonedry ice bath was removed. The mixture was stirred for 30 minutes, and then poured into cold water (1000 ml) and thereto was added ethyl acetate (2000 ml). The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and the solvents were removed. The residue was recrystallized from ethyl acetate to give 2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde (74.8 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([F:35])[CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[C:28]([F:35])[CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1F
Yield: 53.1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (0.6 mg, 0.3%). The same compound was also prepared using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode when 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (63.6 mg, 53%). The second sample was characterized by 1H NMR: (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.50 (d, J=4.9 Hz, 2H), 8.26-8.37 (m, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.37-7.60 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[NH4+].[Cl-]>CC(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:18]2[CH2:17][CH2:16][CH:15]([O:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[C:11]([F:10])([F:25])[F:26])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)c1ccccc1OC1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 100-mL flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (3.80 g, 19.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (6.90 g, 24.5 mmol) and 2-propanol (25 mL). The suspension was treated with N,N-diisopropylethylamine (8.6 mL, 49 mmol) and stirred at room temperature for 10 min and then heated to 100° C. for 16 h. After this time, the mixture was cooled to room temperature, poured into a 250-mL separatory funnel containing saturated aqueous NH4Cl (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude solid was triturated in diethyl ether to yield the title compound as an off-white solid. MS (ESI, Q+) m/z 403, 405 (M+1 for 35Br and 37Br).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[N:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:8]=1)#[N:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:3]1[C:4]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[N:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:8]=1)#[N:2]
Reactant: CCOC(=O)COc1nc(Nc2cc3ccccc3cn2)cnc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ncc(Nc2cc3ccccc3cn2)nc1OCC(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
Ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2-yloxy)acetate (35 mg, 0.099 mmol) was dissolved in THF (1 mL) and lithium hydroxide (2.4 mg, 0.099 mmol) added. The reaction was stirred at room temperature for 15 hours. Methanol (1 mL) was added and the reaction mixture was stirred for a further 24 hours and then concentrated to dryness. Purification by preparative HPLC afforded the title compound (10.8 mg, 0.0336 mmol, 34%). 1H NMR (MeOD, 400 MHz) δ 9.04 (s, 1H), 8.53 (s, 1H), 8.14-8.10 (m, 2H), 7.97 (d, 1H, J=8.0 Hz), 7.72-7.67 (m, 1H), 7.53-7.48 (m, 1H), 4.96 (br s, 2H), 2.67 (s, 1H). LC-MS (2) Rt=1.46 min; No ionization.