Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:13].C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:60][CH2:61][C:62]1[C:67]([CH2:68][CH3:69])=[N:66][C:65]2[N:70]([CH2:73][CH3:74])[N:71]=[CH:72][C:64]=2[C:63]=1[NH:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH2:73]([N:70]1[C:65]2=[N:66][C:67]([CH2:68][CH3:69])=[C:62]([CH2:61][NH:60][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH3:24])=[CH:23][CH:22]=3)[C:63]([NH:75][CH:76]3[CH2:77][CH2:78][O:79][CH2:80][CH2:81]3)=[C:64]2[CH:72]=[N:71]1)[CH3:74]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCN(C)CCO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)benzoic acid (7.38 g, 19.8 mmol, 1.2 equivalents, e.g. which can be as prepared in Intermediate 39) in N,N-dimethylformamide (75 ml, about 10 volumes cf. the weight of the acid) was treated with N,N-diisopropylethylamine (4.89 ml, 3.62 g, 28.1 mmol, 1.7 equivalents) resulting in a clear yellow solution. N,N′-Dicyclohexylcarbodiimide (4.42 g, 21.45 mmol, 1.3 equivalents) and then 1-hydroxybenzotriazole hydrate (3.28 g, 21.45 mmol, 1.3 equivalents) were added, and the mixture was stirred at room temperature for 15 minutes. 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (5 g, 16.5 mmol, 1 equivalent, e.g. which can optionally be as prepared in Intermediate 7 including alternative preparation no. 1 thereof) was then added, resulting in a cloudy yellow/orange solution which was allowed to stir at room temperature overnight. As much N,N-dimethylformamide as possible was evaporated off, the residue was partitioned between dichloromethane and sodium bicarbonate solution, and then the separated aqueous phase was extracted with more dichloromethane. The combined organic extracts were washed with lithium chloride solution, water and brine, were dried (MgSO4), and were concentrated by evaporation, to give the crude product (15.5 g). 1.73 g of this crude product was removed. The remainder of the crude product was purified by column chromatography on silica gel (about 600 g), eluting with 10% methanol in dichloromethane, followed by 20% methanol in dichloromethane, 20% methanol in dichloromethane containing triethylamine, and finally 30% methanol in dichloromethane containing triethylamine. The majority of the fractions containing the product were combined and evaporated to give the title compound (6.68 g) as a white foam. LCMS showed MH+=622; TRET=2.21 min. The apparently-more-pure fractions containing the product were combined and evaporated to give more of the title compound (0.48 g).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.COCCOC.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC(C)(C)C(=O)On1nnc2ccccc21
Temperature: 21 °C

Procedure:
To a mixture of 1-hydroxybenzotriazole (30.6 g), 1,2-dimethoxyethane (150 ml), and pyridine (16 g), there was added, while stirring at 21° C., pivaloyl chloride (24.1 g) during 0.75 hr. During the addition, the temperature of the reaction mixture was raised to 34° C. by the heat evolved. The reaction was then heated externally at 88° C. for an additional 0.5 hr. period then cooled, washed with water, and extracted with 1,1,2-trichlorotrifluoroethane. The extract was dried and stripped of solvent and the residue was column chromatographed on neutral alumina in benzene solvent. The product, 1-benzotriazolyl pivalate, was obtained as a brown oil after removal of the benzene solvent. The elemental analysis was as follows:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][C:14](CCCO)=[CH:13][CH:12]=1.[CH2:21](N(CC)CC)C>ClCCl>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:21][CH2:2][CH:1]=[O:5]
Reactant: CCN(CC)CC
Reactant: OCCCc1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCc1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.5 mL (9 mmol, 1.2 eq.) of oxalyl chloride (2.0 M solution in dichloromethane) was diluted with 15 mL of dichloromethane. To this solution was added a solution of 1.2 mL (17.5 mmol, 2.4 eq.) of DMSO in 3 mL of dichloromethane at −60° C. and the mixture was stirred for 10 minutes at this temperature. To this mixture was added a solution of 1 g (7.3 mmol) of 4-pyridinepropanol in 7 mL of dichloromethane at −60° C. The resulting mixture was stirred at −60° C. for 15 minutes, then 5.0 mL (36.5 mmol, 5.0 eq.) of triethylamine was added at this temperature. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was quenched with water. The organic layer was separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography providing 3-pyridin-2-ylpropionaldehyde as a brown oil.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29])[CH3:24]>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28]([NH:22][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:29])[CH3:24]
Reactant: Nc1cc(-c2ccc(F)cc2)on1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Yield: 832.3 %

Procedure:
Diisopropyl carbodiimide (0.07 mL, 0.45 mmol) and 5-(4-fluoro-phenyl)-isoxazol-3-ylamine (67 mg, 0.037 mmol) were added to a stirred solution of malonic acid monoethyl ester (50 mg, 0.37 mmol) in THF (1 mL) and stirring was continued at reflux temperature for 4 hrs. The mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with water, followed by brine solution. The organic layer collected was dried over Na2SO4 and concentrated under reduced pressure to afford 90 mg (81.8% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11]([NH2:13])=[O:12].C1C2C(=CC=CC=2)C=CN1>>[CH:2]1([C:11]([NH2:13])=[O:12])[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=[CH:10][NH:1]1
Reactant: NC(=O)C1C=Cc2ccccc2N1
Agent: C1=Cc2ccccc2CN1
Product: NC(=O)C1NC=Cc2ccccc21
Yield: 50 %

Procedure:
Following the procedure for preparing amide from example 48, dihydroisoquinoline acid a (1.25 g, 6.2 mmol) prepared according to the procedures described by Deady et al. (J. Heterocyclic Chem. 2001, 38, 1185) afforded 754 mg (50%) of dihydroisoquinoline amide b as a yellow gum.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[CH:12]([NH:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1)[CH2:11][CH2:10]2.[OH2:25].[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[CH:12]([NH:14][C:15]1[C:20](/[CH:21]=[CH:28]/[C:27]([O:26][CH2:30][CH3:29])=[O:25])=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1)[CH2:11][CH2:10]2
Reactant: O
Reactant: C1CCOC1
Reactant: COc1cccc2c1C(Nc1nc(SC)ncc1C=O)CC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(SC)nc1NC1CCc2cccc(OC)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion, 0.21 g, 5.25 mmol) in anhydrous tetrahydrofuran (21 mL) was added dropwise a solution of triethyl phosphonoacetate (1.03 mL, 1.16 g, 5.19 mmol) in anhydrous tetrahydrofuran (5 mL) at 0-5° C. and the reaction mixture was stirred for 30 min at this temperature. To this suspension was added carefully 4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.48 g, 4.69 mmol) in anhydrous tetrahydrofuran (25 mL) below 5° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was cooled to below 5° C. and water (22 mL) was added dropwise. It was diluted further with ethyl acetate (25 mL) and saturated brine solution (15 mL), the two phases were separated, and the organic layer was washed with saturated sodium carbonate solution (1×30 mL), water (1×30 mL), dried over sodium sulfate, filtered and evaporated to give (E)-ethyl 3-(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)acrylate as a light brown solid (2.26 g, 5.86 mmol, quant.). ESMS m/z 386 (M+H)+; 1H NMR (400 MHz, CDCl3), E/Z isomers in a ratio of 90:10, δ ppm 8.15 (s, 0.9H, E), 8.13 (s, 0.1H, Z), 7.46 (d, J=16. e.g., 1 Hz, 0.9H, E), 7.27-7.31 (m, 1H, E+Z), 6.92 (d, J=7.5 Hz, 1H, E+Z), 6.76 (d, J=8.3 Hz, 0.9H, E), 6.73 (d, J=8.3 Hz, 0.1H, Z), 6.57 (d, J=11.8 Hz, 0.1H, Z) 6.27 (d, J=16. e.g., 1 Hz, 0.9H, E), 5.98 (d, J=11.8 Hz, 0.1H, Z) 5.77 (d, J=4.5 Hz, 0.9H, E), 5.58-5.65 (m, 1H, E+Z), 5.17 (d, J=4.5 Hz, 0.1H, Z) 4.23 (q, J=7.2 Hz, 2H, E+Z), 3.83 (s, 2.7H, E), 3.78 (s, 0.3H, Z), 2.99-3.11 (m, 1H, E+Z), 2.85-2.95 (m, 1H, E+Z), 2.71-2.82 (m, 1H, E+Z), 2.57 (s, 2.9H, E), 2.56 (s, 0.3H, Z) 1.99-2.11 (m, 1H, E+Z), 1.30 (t, J=7.2 Hz, 3H, E+Z).
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)O[C@@H](CC1CCCC1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 92.1 %

Procedure:
A solution of 395 mg (1.97 mmol) of 2-(S)-acetoxy-3cyclopentyl propanoic acid (from EXAMPLE 20, Step E) in 10 mL MeOH and 1 mL of H2O was treated with 1.29 g (9.33 mmol) of K2CO3 and stirred at rt for 30 h. The volatiles were removed under reduced pressure. The crude product was partitioned between 100 mL of ether and 100 mL of H2O and the layers were separated. The aqueous layer was acidified to pH 1-2 using 2.0 N HCl and extracted with 3×150 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 287 mg (92%) of the title compound: 1H NMR (300 MHz) δ 1.11-2.15 (m, 11H), 4.27 (dd, J=8.1, 4.7, 1H), 6.5 (br, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cu][C:15]#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:15]#[N:16])([O-:13])=[O:12]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 160 °C
Yield: 20.3 %

Procedure:
3-iodo-5-nitro-1H-indazole (6.9 g, 23.87 mmol) was taken up in NMP (90 mL) and copper (I) cyanide (4.28 g, 47.7 mmol) was added. The reaction was heated at 160° C. for 1 h, then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through celite, rinsing with EtOAc. The filtrate was washed 2× with water and 2× with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 0.91 g of 5-nitro-1H-indazole-3-carbonitrile was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CC(C)(OC([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23](O)=[O:24])=O)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:49]>ClCCl>[ClH:49].[ClH:49].[NH2:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: ClCCCl
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cl
Product: N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Yield: 67 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199 ) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H) 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H) 4.97-5.48 (m, 2H) 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).
Reaction SMILES: [F:1][CH:2]([F:10])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1.F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1.C(N(C(C)C)C(C)C)C.CN(C)C=O>[F:1][CH:2]([F:10])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[CH2:5]1
Reactant: N[C@@H]1CCN(CC(F)F)C1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@@H]2CCN(CC(F)F)C2)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
To a solution of EXAMPLE 407B (468 mg) in tetrahydrofuran (20 mL), N-ethyl-N-isopropylpropan-2-amine (2.193 mL) and N,N-dimethylformamide (2 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (473 mg) and the reaction mixture was stirred 72 hours. The crude product was isolated by concentration and was purified on silica gel, and was eluted with a 0.5, 2.5, and 5% methanol in methylene chloride step gradient to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10](C)[C:11](=O)OC(C)(C)C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1cc(Br)cn(C)c1=O
Temperature: 30 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30° C. The reaction mixture was stirred at 30° C. for 30 min. The mixture was filtered and the filter cake collected. The filtrate was adjusted to pH=9 with saturated aqueous NaHCO3, extracted with ethyl acetate (20 mL), dried over Na2SO4, filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg). 1H NMR (CDCl3 400 MHz): δ 6.74 (d, J=2.4 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 5.15 (s, 1H), 3.53 (s, 3H), 2.83 (s, 3H). LCMS (M+H)+ 217.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:18]#[N:19])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: Cc1cc(CBr)ccc1NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(CC#N)ccc1NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
The compound (155.1 mg) obtained in Example 519 was dissolved in dimethyl sulfoxide (5 ml). To the solution, sodium cyanide (127 mg) was added and the mixture was heated at 50° C. under stirring for 10 min. To the resulting reaction mixture, ethyl acetate was added and the organic layer was washed with water twice, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 77.7 mg of the titled compound (yield, 61%).
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>CN(C=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[N:3]=[C:1]([NH2:2])[O:18][N:17]=2)[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(Nc2cc(Cl)cc(Cl)c2)no1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 10.2 %

Procedure:
In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00), hydroxylamine hydrochloride (347 mg, 5 mmol, Eq: 8.33) and triethylamine (506 mg, 697 μl, 5 mmol, Eq: 8.33) were combined with DMF (6 ml) to give a white suspension. The vial capped and stirred in a 50° C. oil bath for 3.5 hours. The reaction was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product, was recrystallized from EtOH then dried in vacuo (80° C., 2 torr, overnight) to give 15 mg (10%) of desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:16]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Yield: 60 %

Procedure:
2,4 dichloropyrimidine and 3-formyl phenyl boronic acid were coupled following procedure A. The yield was 60%. LC-MS showed the product was >95% pure and had the expected M+H+ of 219. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ10.1 (s, 1H) 8.7 (d, 1H) 8.6 (m, 1H) 8.4 (m, 1H) 8.1 (m, 1H) 7.7 (m, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(Cl)Cl>O.C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([S:11][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: ClCc1cccnc1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Clc1cc(Cl)cc(SCc2cccnc2)c1
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Sodium hydroxide (0.154 g. 3.85 mmol) in 2 mL water was added to 3,5-dichloro-benzenethiol (0.328 g, 1.83 mmol) in 5 mL of ethanol. After 10 min stirring, 3-chloromethyl-pyridine hydrochloride (0.301 g, 1.83 mmol) in 2 mL water was added slowly. The resulting reaction mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture. The organic phase was washed with saturated aqueous sodium bicarbonate solution and brine. After removal of the solvent, the crude product was purified with flash chromatography to give 0.470 g (95% yield) of 3-(3,5-dichloro-phenylsulfanylmethyl)-pyridine. This compound was converted to N-[3-(1H-indol-4-yl)-5-(pyridin-3-ylmethylsulfanyl)-phenyl]-acetamide as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 8.42 (s, 1H), 8.35 (d, J=4.7 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.66 (s, 2H), 7.38-7.31 (m, 2H), 7.27-7.23 (m, 2H), 7.13 (t, J=7.7 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 4.20 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28]>>[CH3:28][CH:27]([CH2:26][C@H:25]([OH:30])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH3:29]
Reactant: CC(C)CC=O
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)C[C@H](O)C=CC(C)(C)C
Yield: 86 %

Procedure:
The product was prepared by General procedure S using 196 mg (1.1 mmol) Cy2BH, 137 μL (1.1 mmol) 3,3-dimethyl-1-butyne, 1.1 mL (2.1 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 107 μL (1.0 mmol) isovaleraldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 86% yield (146 mg, 0.86 mmol). [α]D20=+16.7 (c=3.0, CHCl3, 85% ee); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 6H, J=7.0 Hz), 0.97 (s, 9H), 1.26 (m, 1H), 1.43 (m, 1H), 1.50 (br s, 1H), 1.65 (m, 1H), 4.07 (dt, 1H, J=7.0, 6.8 Hz), 5.31 (dd, 1H, J=15.6, 7.2 Hz), and 5.61 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 1.25 MHz): δ 22.5, 22.9, 24.6, 29.5, 32.5, 46.6, 71.5, 128.1, and 142.6 ppm; IR (neat): 3334, 3013, 2956, 2869, 2354, 2320, 1662, 1466, 1386, 1363, 1308, 1268, 1220, and 1202 cm−1; HRMS-CI m/z 170.1666 [M+; calcd for C11H22O: 170.1671].
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([N:15](CC)CC)[CH3:14].C(Cl)(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:13]([CH3:14])[NH:15][C:4]2=[O:6]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(=O)[nH]c(C)nc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-3-methoxybenzoic acid (10.3 g), 4-dimethylaminopyridine (0.65 g) and triethylamine (34.3 ml) in N,N-dimethylformamide (60 ml) was added acetyl chloride (10.5 ml) at 3°-15° C. for 20 minutes. Then the reaction mixture was heated at 90° C. After 3 hours, to the reaction mixture was added portionwise ammonium carbonate (17.7 g) for 10 minutes. The mixture was stirred at the same temperature for 1 hour. Cooling the mixture, water (300 ml) was added thereto. The precipitate was collected by filtration, washed with water and acetonitrile to give 8-methoxy-2-methyl-4-oxo-3,4-dihydroquinazoline (9.24 g) as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]([OH:33])[CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[OH:20])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C

Procedure:
To a stirring solution of diisopropylamine (14.9 g, 19.4 mL, 148 mmol) in tetrahydrofuran (500 mL) at -78° C. was added, dropwise, n-butyllithium (59 mL of a 2.5M solution in tetrahydrofuran). After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (30 g, 134 mmol) in tetrahydrofuran (150 mL) was added dropwise and the temperature allowed to rise to -15° C. The solution was again cooled to -78° C. and a solution of 3,4-dichlorobenzaldehyde (25.9 g, 134 mmol) in tetrahydrofuran (150 mL) added dropwise. After the solution was allowed to warm to -20° C., it was poured into saturated aqueous sodium hydrogen carbonate (2 L). The aqueous layer was extracted with ethyl acetate (3×400 mL), the combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran (400 mL) and to this solution was added tetrabutylammonium fluoride (148 mL of a 1.0M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil chromatographed on silica gel, eluting with 95:5 dichloromethane:methanol to give the title compound as a mixture of diastereomeric diols as a foam (31.7 g) which was used without further purification.