Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([CH2:12][C:13](=[S:15])[NH2:14])#[N:11]>CN(C)C=O>[C:10]([CH2:12][C:13]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)#[N:11]
Reactant: N#CCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(CC#N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a solution of ethyl 3-bromo-2-oxopropanate (21 g, 110 mmol) in N,N-dimethylformamide (50 mL) was added a solution of 2-cyanoethanethioamide (10 g, 100 mmol) in N,N-dimethylformamide (50 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (5.1 g, 26%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([O-:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3cccc(C(=O)[O-])c3[nH]2)cc1
Reactant: N
Product: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
The acetate salt of methyl (2-(4'-methoxyphenyl)benzimidazole-4-carboxylate was dissolved in excess liquid ammonia and heated at 100° C. in a sealed pressure vessel at 40 atmospheres overnight. The ammonia was allowed to evaporate, and the solid residue was collected and washed with ice cold water (3×5 ml). Recrystallisation from aqueous methanol afforded the title compound (226.4 mg, 80%); mp 261-263° C.; Found: C, 66.07; H, 4.23; N, 15.29. C15H13N3O2. 0.2CH3OH requires C, 66.70; H, 5.08; N, 15.35; vmax /cm-1 3321.47, 3140.72, 1656.23, 1608.25, 1421.43, 1242.55; δH (d6DMSO, 200 MHz) 3.96 (3H, s, OMe), 7.23-7.27 (2H, d, J=8.6, Ph-3/3'H), 7.37-7.45 (1H, t, Ar-5H), 7.78-7.82 (1H, d, Ar-4H), 7.87 (1H, br s, Imz-H), 7.93-7.96(1H, d, Ar-6H), 8.27-8.31 (2H, d, J=8.6, Ph-2/2'H), 9.4-9.5 (1H, br s, --CONH), 13.3-13.4 (1H, br s, --CONH); m/z (EI) 267 (M+), 249, 222, 206, 77, 32.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH3:23])[C:19]([NH:64][C@@H:63]([CH2:62][S:61][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:65]([NH2:67])=[O:66])=[O:21])=[CH:31][CH:32]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.24 g (3.86 mmol) of the compound from example 7A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71% of theory, 78% purity) of the desired product as a mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:42]=[N:41]C=2C=1.O.NN>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([NH:41][NH2:42])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NN)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.9 %

Procedure:
A mixture of 4-(1-phenyl-1-carboxy-methylene)piperidine-1-carboxylic acid tert-butyl ester (0.153 g, 0.048 mol), EDCI (0.113 g, 0.059 mol), and HOBt (0.081 g, 0.060 mol) in DMF (3 mL) was stirred for 30 min at room temperature and then hydrazine hydrate (1.0 mL) was added. Stirring was continued for 12 h and then the mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed, (H2O ×5, brine) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (0.147 g, 92%) as a colorless oil:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH3:22])[C:17](I)=[C:18]([CH3:20])[CH:19]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:13][C:14]1[CH:15]=[C:16]([CH3:22])[C:17]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2.5 M n-Butyllithium, in tetrahydrofuran, (1.42 ml, 3.54 mmol, 1.1 equiv.) was added dropwise to a solution of bromobenzene (0.34 ml, 3.22 mmol, 1.0 equiv.) in dry tetrahydrofuran (18 ml), under nitrogen at −78° C. and the mixture stirred for 30 minutes. Zinc chloride (0.48 g, 3.54 mmol, 1.1 equiv.) was added and the mixture allowed to warm to room temperature while stirring for 2 hours. Palladium tetrakistriphenylphosphine (0.19 g, 0.16 mmol, 0.05 equiv.) and a solution of 5-bromo-2-iodo-1,3-dimethyl-benzene (1.00 g, 3.22 mmol, 1.0 equiv.) in tetrahydrofuran (2 ml) were added and the mixture stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the crude product purified by column chromatography (SiO2, heptane). The fractions were combined to afford 4-bromo-2,6-dimethylbiphenyl, 278 mg (33% yield) as a clear oil δH (400 MHz; d4-methanol) 7.28-7.39 (3H, m), 7.18 (2H, s), 7.03 (2H, d), 1.90 (6H, s).
Reaction SMILES: [N+](=[CH:3]P(=O)(OC)OC)=[N-].CC(C)([O-])C.[K+].[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([CH:40]=O)[CH2:35][CH2:34][C:33]4([O:39][CH2:38][CH2:37][O:36]4)[CH2:32][CH2:31]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([C:40]#[CH:3])[CH2:31][CH2:32][C:33]4([O:36][CH2:37][CH2:38][O:39]4)[CH2:34][CH2:35]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COP(=O)(C=[N+]=[N-])OC
Reactant: COc1ccc(C2(C=O)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at -78° C. under an argon atmosphere. To this was added rapidly a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 mL). After 2 h, the reaction was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was washed with brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate provided a white solid. mp 53.5°-55° C.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.CO.[CH3:34][N:35]([CH:37]=O)C>[Pd]>[NH:35]1[CH2:37][CH2:31][CH:11]([NH:10][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:12][CH2:34]1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCNCC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Steps 3 & 4: To the solution of (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-[(5-fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (A4) (0.2 g, 0.48 mmol) in 25 mL of DMF solution was added compound 6c (0.268 g, 0.58 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. 200 mg of 5% Pd/C was added to the mixture, followed by 25 mL of MeOH. The mixture was stirred under H2 atmosphere for 30 min and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol (5 mL*2), dried under vacuum to provide the title compound (80 mg, 43.7% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.67 (s, 1H), 10.89 (s, 1H), 7.67-7.78 (m, 3H), 6.82-6.96 (m, 2H), 3.87-3.92 (m, 1H), 3.06-3.09 (d, 2H), 2.72-2.79 (t, 2H), 2.39-2.41 (ds, 6H), 1.84-1.89 (d, 6H), 1.46-1.57 (m, 2H). LC/MS: 383.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH2:24]1[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:25]1>>[CH2:21]([O:20][C:18]([C:15]([CH3:17])([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]4[O:33][CH2:34][CH2:24][O:25][C:26]=4[CH:27]=3)[N:7]=2)=[CH:10][CH:11]=1)=[O:19])[CH3:22]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Cl)ncc2F)cc1
Product: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz), 6.98 (dd, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, J=8.2 Hz), 4.19-4.15 (m, 4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz). LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH+).
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1.C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[CH3:34])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][N:2]1[C:6]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-c2ccccc2)n(C)c1C=NOCCO
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)n(C)c1C=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 73.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 420 mg of 2-(1,4-dimethyl-2-phenylimidazol-5-ylmethyleneaminooxy)ethanol (prepared as described in Preparation 24), 580 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 425 mg of triphenylphosphine and 282 mg of diethyl azodicarboxylate, 646 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[S:10](Cl)(Cl)=O>C(Cl)(Cl)Cl.CO>[NH2:9][C:6]1[C:7]2[C:2](=[N:1][S:10][N:8]=2)[N:3]=[CH:4][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnc(N)c1N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2nsnc12

Procedure:
A flask was charged with 19.78 g. (0.15 mole) of 4,5,6-triaminopyrimidine and 163.0 g. (137 mole) of thionyl chloride and the mixture stirred at reflux for 18 hours. The dark orange reaction mixture was evaporated to dryness on the rotary evaporator and to the residue was added 500 ml. water and 40 ml. methanol. The resulting solution was adjusted to a pH of 7.5-8.0 with saturated sodium bicarbonate solution and heated to reflux. The hot mixture was filtered and the filtrate cooled to 0°-5° C. in an ice-bath. The solid was collected by filtration, washed twice with 50 ml. ice water and twice with 50 ml. ether. The resulting tan product was dried in vacuo at 70° C. overnight to afford 18.2 g. (79%) of product. M.p. 247°-249° C.; tlc on silica gel in chloroform-methanol (8:1) showed one spot at Rf =0.4.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:12]([NH:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH:13]=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[N:15]([CH2:12][CH:13]=[CH2:14])[CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCCC(C)NCC=C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to a stirred solution of allyl-(1-methyl-pent-4-enyl)-amine (7 g, 50 mmol), triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH2Cl2 (100 ml) at 0 C. The reaction mixture was warmed to RT, then was stirred for 2 h. The reaction mixture was diluted with CH2Cl2 (100 ml), then was extracted with water, then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 4% EtOAc/hexanes) to give the title compound (8.9 g, 65% yield): Liquid Chromatgraphy/Electrospray mass spec: M+H+=274.2
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-]>O1CCCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)c(OC)c1

Procedure:
A stirred suspension of magnesium (8.11 g) in dry tetrahydrofuran (100 mL) is heated, and then treated with a solution of 1-bromo-2,4-dimethoxybenzene (48 mL) in tetrahydrofuran (100 mL) at such a rate as to maintain reflux. The resulting solution is then cooled and added, dropwise, to a solution of 2-bromopyridine (50.3 g) and bis-triphenylphosphinepalladium(II) chloride (3.5 g) in tetrahydrofuran (100 mL) at reflux, and the mixture is maintained at reflux for 6 hours. The solution is then evaporated and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give a dark oil. This is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (2:1 v/v) to give 2-(2,4-dimethoxyphenyl)pyridine (28 g) in the form of an oil. [NMR(CDCl3):- 3.84(3H,s),3.86(3H,s), 6.55(1H,s),6.6(1H,d),7.2(1H,m),7.7(1H,t),7.77 (1H,d),7.8(1H,d),8.7(1H,d)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[OH:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[O:11][CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])=[O:5])[CH3:2]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1c(CC)n[nH]c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)n[nH]c1OC(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-ethyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 8.14 mmol) in DMF (10 ml) is added K2CO3 (1.15 g, 8.14 mmol). The mixture is heated to 50° C. and treated with a solution of 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (2.53 g, 8.96 mmol) in DMF (10 ml). Stirring continues at 50° C. for 1 hour and after cooling to RT, the reaction mixture is poured into water (300 ml, pre-cooled to 10-15° C.) which is subsequently allowed to reach ambient temperature over 3 h (with stirring). The resulting suspension is filtered, washed with water and the solid dried in vacuo overnight. The resultant crude product is triturated in diethyl ether (approx. 15 ml) for 20 mins. then dried in vacuo to yield 5-[2-(2,4-dichloro-phenyl)-1-methyl-2-oxo-ethoxy]-3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester: yield: MS: m/z 385.13 [M+H]+
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH3:13][C:14]([CH3:16])=O>>[CH3:13][C:14]1([CH3:16])[O:9][CH:8]([CH:6]2[O:7][C:2]([CH3:4])([CH3:1])[O:5][CH:4]2[CH:2]2[O:3][C:8]([CH3:10])([CH3:6])[O:12][CH2:1]2)[CH2:10][O:11]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 58 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To 250 ml of acetone were added 10.0 g of D-mannitol and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 8 hours under reflux in a warm-water bath at 58° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the acetone was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the chloroform was distilled under reduced pressure, there was obtained 16.0 g (96.4%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol (purity of not less than 92%). The compound, when recrystallized from 70% ethanol, showed a melting point of 68.5° to 70.5° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]#[N:29])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:30].[K+]>CC(O)(C)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:29])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccc(F)cc4)cc23)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(F)cc4)cc23)CC1
Reaction time: 0.02 h
Yield: 47.8 %

Procedure:
The mixture of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluorophenyl)-1H-indazole-7-carbonitrile (Intermediate 11) (0.102 mmols) and potassium hydroxide (26 mg, 0.51 mmol) in 2-methyl-2-propanol (4 mL) was heated overnight. The reaction mixture was concentrated and purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 70% B in 3.2 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (21 mg, 48% for 2 steps)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)[CH3:9])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[S:34])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=S)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
A mixture the product of Step A (3 g, 8.5 mmol) and Lawesson's reagent (1.7 g, 4.25 mmol) in toluene (100 ml) was refluxed for 2 h. The mixture was cooled to room temperature and then was diluted with EtOAc (100 ml), washed with 1N NaOH (2×50 ml), dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (DCM/MeOH gradient, 0-15% MeOH) provided the desired product as a white solid (2.2 g, 71%)