Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13])=[N+:2]=[N-:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)CCC>[CH3:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]1[CH:21]=[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[N:2]1
Reactant: COCCOCCOCCN=[N+]=[N-]
Reactant: C#Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: COCCOCCOCCn1cc(-c2ccccc2)nn1

Procedure:
1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane (15.0 g, 79 mmol) was mixed with phenylacetylene (8.10 g, 79 mmol) in a 1:3 solution of water:butanol. The mixture was rotovap and the product extracted in ethanolamine and washed multiple times with water and brine, producing 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-phenyl-1H-1,2,3-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N:17]=[C:18]=[O:19])[CH:14]=[CH:13][C:3]=1[C:4]([O:6]C1CCCCC1)=[S:5].[CH3:20][NH:21][CH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[O:19])[CH:14]=[CH:13][C:3]=1[C:4]([S:6][CH:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:3]1)=[O:5]
Reactant: O=C=Nc1ccc(C(=S)OC2CCCCC2)c(Cl)c1
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(C(=O)SC2CCCCC2)c(Cl)c1
Reaction time: 8 h

Procedure:
20 g of cyclohexyl 2-chloro-4-isocyanatothiobenzoate in 80 ml of toluene were added dropwise to excess aqueous dimethylamine solution at room temperature. The mixture was kept at room temperature, stirred overnight and then filtered under suction. 16.3 g of N-(3-chloro-4-cyclohexylmercaptocarbonylphenyl)-N',N'-dimethylurea (compound no. 35) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH:17]12[O:22][CH:21]1[CH2:20][CH2:19][CH2:18]2>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C@@H:20]2[CH2:19][CH2:18][CH2:17][C@H:21]2[OH:22])[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: C1CC2OC2C1
Reactant: O=S(=O)(c1ccccc1Cl)N1CCNCC1
Solvent: CCO
Product: O=S(=O)(c1ccccc1Cl)N1CCN([C@@H]2CCC[C@H]2O)CC1
Temperature: 80 °C

Procedure:
1-(2-Chlorophenylsulfonyl)piperizine (1 eq, 0.19 mmol) was dissolved in ethyl alcohol (2 ml), then treated with 6-oxa-bicyclo[3,1,0]hexane (2eq, 0.38 mmol), the reaction solution was heated to 80° C. for 8 hour. The reaction mixture was purified by prep-HPLC. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.36-1.48 (m, 1 H), 1.49-1.74 (m, 3 H), 1.81-2.03 (m, 2 H), 2.52-2.67 (m, 3 H), 2.68-2.78 (m, 2 H), 3.28-3.37 (m, 4 H), 3.99-4.18 (m, 1 H), 7.33-7.42 (m, 1 H), 7.44-7.58 (m, 2 H), 7.98 (d, J=8.21, 1.14 Hz, 1 H); ESI-MS: m/z 345 (m+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:15](O)=[C:16]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:17]([C:29]#[N:30])=[C:18]([CH3:28])[C:19]=1[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:19]([CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([CH3:28])[C:17]([C:29]#[N:30])=[C:16]2[C:15]=1[O:37][C:32]([C:33]([CH3:36])([CH3:35])[CH3:34])=[N:31]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C=Cc2ccccc2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 84.3 %

Procedure:
Toluene (3 ml), p-toluenesulfonic acid monohydrate (1.4 mg, 7.5 μmol) were added to N-(3-bromo-6-cyano-2-hydroxy-5-methyl-4-styrylphenyl)-2,2-dimethylpropionamide (I-14) (31 mg, 75 μmol), followed by refluxing with a Dean-Stark condenser for 2.5 hours. After cooling, saturated sodium bicarbonate water (30 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (30 ml×2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the entitled compound (25 mg, 84%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[Li]CCCC.Cl[P:22]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:29]1([P:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: COc1ccccc1-c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A solution of 2-bromo-2′methoxy-1,1′-biphenyl (535 mg, 2.03 mmol) in THF (20 mL) was cooled to −78° C. under argon, then n-BuLi (1.6 M in hexane, 1.35 mL, 2.16 mmol) was added dropwise. After 2.5 h at −78° C., a solution of chlorodicyclohexylphosphine (570 mg, 2.45 mmol) in THF (3 mL) was added over 10 min. The reaction mixture was then allowed to warm to room temperature overnight, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The resulting aqueous suspension was extracted with ether (2×50 mL), and the combined ethereal layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude solid was recrystallized from ethanol to afford 420 mg (54 %) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@@H:24]([CH2:32][OH:33])[NH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([C:7]([N:23]2[C@H:24]([CH2:32][OH:33])[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)=[O:9])[CH:10]=1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To an ice cooled solution of 5-bromo-2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)benzoic acid (45.0 g, 127.8 mmol) in DCM (450 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (20.8 g, 102.27 mmol), HATU (72.7 g, 191.2 mmol), DIPEA (55.7 mL, 319.6 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with DCM (750 mL), washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the the title compound as a liquid 50 g (79%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-7.00 (m, 4H), 6.80-6.40 (m, 1H), 5.10-3.80 (m, 7H), 3.50-2.40 (m, 3H), 2.40-2.10 (m, 3H), 1.30-1.00 (m, 3H); ES-MS: m/z 498.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH:7]=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH:7]=[N:12][NH:13][C:14]([NH2:16])=[S:15]
Reactant: O=CC=Cc1cccc(O)c1
Reactant: NNC(N)=S
Product: NC(=S)NN=CC=Cc1cccc(O)c1
Yield: 28 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-hydroxycinnamaldehyde (6 mmoles) and from thiosemicarbazide (6 mmoles). Yield 28%.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])([CH3:3])[CH3:2].[H][H]>[Pd]>[CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(2-isopropoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.17 g) was reduced with hydrogen and Pd/C (350 mg). The crude product (1.086 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 6.92 (d, 1H), 6.85 (d, 1H), 3.45 (m, 1H), 3.39 (t, 2H), 3.10 (t, 2H), 1.05 (d, 6H).
Reaction SMILES: O[CH:2]1[CH2:6][N:5]([C:7](=[O:24])[CH2:8][P:9]([O:21][CH2:22][CH3:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[C@H:4]([C:25]([O:27][CH3:28])=[O:26])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:48]=[N+:49]=[N-:50].C1C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.N=[N+]=[N-]>C(#N)C>[N:48]([CH:2]1[CH2:6][N:5]([C:7](=[O:24])[CH2:8][P:9]([O:21][CH2:22][CH3:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[C@H:4]([C:25]([O:27][CH3:28])=[O:26])[CH2:3]1)=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=N
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(O)C[C@H]1C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC#N
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(N=[N+]=[N-])C[C@H]1C(=O)OC
Reaction time: 18 h

Procedure:
(S)-4-Hydroxy-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, methyl ester (2.0 g), triphenylphosphine (2.57 g), 2.1 N hydrazoic acid/benzene (12 ml, >5 equivalents) and dry acetonitrile are stirred under argon at room temperature for 30 minutes. Diethylazocarboxylate (1.71 g) in acetonitrile (5 ml) is added dropwise over 30 minutes. After 18 hours the reaction is still incomplete (as shown by thin-layer chromatography) and triphenylphosphine (1 equivalent), diethylazocarboxylate (1 equivalent) and 2.1 N hydrazoic acid (6 ml) are added. After 4 hours the reaction is complete. Nitrogen is bubbled through the solution to remove excess hydrazoic acid and the solvent is stripped leaving an oil. The oil is chromatographed on 100 mg of silica gel, eluting first with ethyl acetate and then with 3% methanol/ethyl acetate to give 1.64 g of the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.[Br:13][CH2:14][CH2:15]Br>C(O)C>[Br:13][CH2:14][CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2
Reactant: BrCCBr
Reactant: Oc1ccc2nonc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: BrCCOc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
Sodium hydroxide (40 mg, 1 mmol) was added to a solution of 5-hydroxybenzofurazan (136 mg, 1 mmol) in ethanol (2 ml) and the mixture was stirred at room temperature for 30 min. 1,2-dibromoethane (0.26 ml, 0.56 g, 3 mmol) was added and the mixture was heated under reflux for 20 hr., cooled and the solvent was evaporated under reduced pressure. Aqueous sodium bicarbonate (saturated, 10 ml) was added and the mixture was extracted with dichloromethane (3×10 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/10% EtOAc to give the benzofurazan as a pale yellow oil (99 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1.[Si:15]([O:22][C@H:23]1[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]1[F:34])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Si:15]([O:22][C@H:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])=[CH:4][N:3]=2)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]1[F:34])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1ccc(C)n1-c1cnc(Br)cn1
Reactant: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2cnc(-n3c(C)ccc3C)cn2)CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 150.6 %

Procedure:
To a 1 L flask was added 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine (23 g, 67 mmol), (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexanecarboxylate (28 g, 83 mmol), {[P(t-Bu)3]PdBr}2 (800 mg, 1 mmol) followed by toluene (250 mL). The reaction mixture was degassed three times by purging with nitrogen and then cooled to −35±5° C. To the reaction mixture was added NaHMDS (47 mL, 2 M in THF, 94 mmol), dropwise. The temperature was raised to room temeperature over a one hour period and stirred for a further 30 minutes. The reaction mixture was quenched with 8% aqueous ammonium chloride (200 mL), the phases separated, and the aqueous layer extracted with heptane (300 mL). The combined organic layer was washed with 10% brine (400 mL), concentrated under reduced pressure(45±5° C., 50˜100 mbar) to give 48 g of (1RS,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-1-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazin-2-yl)-3-fluorocyclohexanecarboxylate as a mixture of 1R and 1S diastereomers. This material was used for next step without further purification. HPLC retention time=8.274 min HPLC method d: Instrument: Agilent Technologies 1200 series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35° C. Flow rate: 0.70 mL/min. Detection: 210 nm/DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B. LC-MS method: [M+H]+=476.2706, 1H NMR (400 MHz, DMSO-d6): 8.47 (s. 1H), 8.43 (s, 1H), 5.85 (s, 2H), 4.39˜4.52 (m, 1H), 4.14 (dd, J=12 Hz, J=8 Hz, 2H), 3.59˜3.66 (m, 1H), 2.28˜2.94 (m, 1H), 2.06 (s, 6H), 1.84˜1.97 (m, 3H), 1.46˜1.52 (m, 3H), 1.14˜1.17 (t, J=12 Hz, J=8 Hz, 2H), 0.81 (s, 9H), 0.01 (d, J=4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(-c2cn(-c3cc(C(=O)O)ccc3C)nn2)cn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(C)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 7 was prepared by coupling 4-methyl-3-[4-(6-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 547 [C28H32N6O4S+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Cl)cc2)c1C(=O)OCC

Procedure:
A solution of 2-Amino-4-(4-chloro-phenyl)-thiophene-3-carboxylic acid ethyl ester (4a) (1.759 g, 6.24 mmol) in diethyl malonate (8.0 g, 50 mmol) was heated at 180° C. for 4 hours. The excess diethyl malonate was removed under reduced pressure to give the title compound. MS (DCI/NH3) m/e 396 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 12.21 (s, 1H), 7.33–7.20 (m, 5H), 6.62 (s, 1H), 4.31 (q, J=7.12, 2H), 4.15 (q, J=7.12, 2H), 3.61 (s, 2H), 1.33 (t, J=7.12, 3H), 0.99 (t, J=7.12, 3H).
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:15][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: CC(C)(N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1CC(=O)NC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
Into a 300 ml four-necked flask, there were charged benzene (200 ml), 4-fluoro-α,α-dimethylbenzylamine (7.7 g) and triethylamine (6.0 g), and o-methylphenylacetyl chloride (9.5 g) was dropwise added thereto at room temperature while stirring, followed by refluxing for 3 hours. After cooling, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 11.3 g of N-(4-fluoro-α,α-dimethylbenzyl)-o-methylphenylacetamide (Compound No. 11). M.P., 150°-151° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)(C)[CH3:7])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[C:38]([O:40]C)=[O:39])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(O)C.[Li+].[OH-]>C1COCC1>[CH2:6]([N:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[C:38]([OH:40])=[O:39])[CH3:7]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(c1ccc2ccccc2c1C(=O)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Macroporous polystyrene-bound triphenylphosphine resin (56 mg, 0.17 mmol) was treated with di-tert-butyl azodicarboxylate (29 mg, 0.13 mmol) in THF (0.5 mL), shaken at ambient temperature for 15 minutes, treated with a solution of Example 98A (30 mg, 0.08 mmol) in THF (1 mL), shaken at ambient temperature for 15 minutes, treated with ethanol (0.006 mL, 0.11 mmol), shaken for 16 hours at 60° C., filtered, and concentrated. The residue was dissolved in 2:1 dioxane/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 391 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.92 (m, 1H), 7.81 (br s, 2H), 7.64 (br s, 2H), 7.46 (t, 2H), 7.02 (d, 1H), 3.60 (br s, 2H), 0.99 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[N:5][N:6]2[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[N:8][C:7]=12)#[N:2].[BH4-].[Na+]>C(Cl)Cl.CO>[OH:13][CH2:12][CH:10]1[CH2:11][N:6]2[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:3]([C:1]#[N:2])=[C:7]2[NH:8][CH2:9]1
Reactant: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
To a solution of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (250 mg, 0.65 mmol) in DCM (5 mL) and CH3OH (5 mL) was added NaBH4 (250 mg, 6.5 mmol). After stirring at RT for 16 hr, the mixture was partitioned between DCM/CH3OH (100 mL/5 mL) and brine (100 mL). The organic layer was separated from aqueous layers, dried over Na2SO4 and concentrated to afford 250 mg (100%) of 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile. MS (ESI) m/e [M+1]+346.9.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]([OH:11])=[O:10])[CH2:6][O:7][CH3:8])(=[O:3])[CH3:2].[OH-].[Na+].Cl>O>[C:1]([NH:4][C@H:5]([CH2:6][O:7][CH3:8])[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: COCC(NC(C)=O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC[C@@H](NC(C)=O)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
In a vessel, equipped with a magnetic stirrer and pH controller, N-acetyl-O-methyl-D,L-serine (3 g) was dissolved in demineralized water (30 mL) and the pH was adjusted to 7.5-8.0 with 5N sodium hydroxide solution. Acylase I from Porcine Kidney (EC: 3.5.1.14) (50 mg) was added and the solution maintained at 25° C. under mild agitation overnight. The pH was adjusted to 2.7 with concentrated HCl and the aqueous solution injected onto Dowex™ 50WX4-50 ion exchange resin (50 mL) conditioned at pH 3.8. The resulting material was eluted with water at pH 2.4. The aqueous solution thereby obtained was then evaporated to dryness under vacuum to afford the title compound (1.5 g, 50%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12.[H-].[Na+].[CH3:15]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:15])[CH:10]=[C:11]([I:12])[C:3]=12
Reactant: Cc1cc(Cl)c2c(I)c[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c2c(I)cn(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask under N2 gas, 4-chloro-3-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine (D12) (1.48 g, 5.06 mmol) was dissolved in THF (25 mL) and cooled to 0° C. To this was added NaH (0.405 g, 10.12 mmol) portion wise. After 30 minutes of stirring, methyl iodide (0.633 mL, 10.12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 mins and at RT for 1 hour.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NN1CCOCC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCOCC2)[nH]n1
Yield: 27 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (33 mg, 27%) which was obtained as a colorless oil. MS: m/e=364.4 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccncn1

Procedure:
A solution of methanesulphonyl chloride (137 mg) in dichloromethane (2 ml) was added to a solution of 4-(2-hydroxyethyl)pyrimidine (124 mg) (prepared by the method of C. G. Overberger and I. C. Kogon, JACS, 76, 1879 (1954)) and triethylamine (121 mg) in dichloromethane (10 ml), the mixture stirred at room temperature for 3 hours and evaporated under reduced pressure to give the crude title compound as a pale yellow oil which was used directly in Example 10 without further purification.