Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1>CN(C=O)C>[OH:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:8]([C:5]2[C:4](=[O:11])[N:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])=[CH:48][CH:49]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.70 g, 7.35 mmol), HOAT (1.2 g, 8.82 mmol), and EDCI (1.68 g, 8.82 mmol) in DMF (40 mL) was added Et3N (2.6 mL, 18.38 mmol) drop wise. The solution was stirred at rt for 20 minutes, then a solution of 4-aminophenol (994 mg, 9.11 mmol) in DMF (6 mL) was added drop wise to the reaction system. The reaction was heated at 70° C. for 5 hours, then concentrated to 2 mL in vacuo, and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (2.02 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH3:21])[N:14]=[C:15]([OH:18])[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>C1COCC1>[N:39]1([O:18][C:15]2[C:16]3[N:17]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(On2nnc3ccccc32)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (200 mg), BOP (479 mg) and DIEA (314 μl) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silicon gel column chromatography (eluting with EtOAc/CH2Cl2) to provide (R)-4-(1-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[CH3:17][C:18]1[C:22]([CH2:23]Cl)=[C:21]([CH3:25])[O:20][N:19]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:23][C:22]3[C:18]([CH3:17])=[N:19][O:20][C:21]=3[CH3:25])=[N:6][C:5]=2[N:16]=1
Reactant: Cc1noc(C)c1CCl
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: Cc1noc(C)c1CSc1nc(N[C@H](C)CO)c2sc(N)nc2n1

Procedure:
The titled compound was prepared from the product of example 4, step (b), and 3,5-dimethyl-4-chloromethylisoxazole using the method of example 4, step (c) to give a white powder (0.016 g)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:18][CH:15]2[CH2:17][CH2:16]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 2-chloro-5-(chlorosulfonyl)benzoic acid (4.0 g, 15.68 mmol) in DCM (60 mL) was added cyclopropyl amine (1.8 g, 31.57 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mass was concentrated and the residue was diluted with ice cold water and acidified with dilute HCl. The crude solid was filtered off, washed with water and dried to afford 3.0 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.37 (s, 2H), 0.49 (d, J=5.4 Hz, 2H), 2.12-2.13 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 8.18 (s, 1H), 13.92 (br s, 1H).
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1C=CC(S(O[CH2:43][C@@H:44]2[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:43][C@@H:44]6[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]6)[CH:25]=5)[N:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Temperature: 90 °C

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-hydroxyphenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (42 mg, 0.10 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (34 mg, 0.12 mmol) in DMF (1 mL) was added Cs2CO3 (65 mg, 0.20 mmol). The mixture was heated at 90° C. for 4 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness to yield (R)-1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(6-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-phenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:22](OCC)=[O:23])[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([CH3:21])=[C:19]([CH3:27])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 155°-157° C.,
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][S:23]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Reactant: O=S(=O)(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCl)c2n1
Yield: 98.3 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.57 g, 9.80 mmol) (Intermediate 10.1), chloromethanesulfonyl chloride (2.00 ml, 19.59 mmol), and N,N-diisopropylethylamine (11.98 ml, 68.58 mmol) in dichloromethane (100 ml) is stirred for 20 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 3.61 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.05 min (tR(SM) 6.64 min). 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.56 (m, 2H), 6.93 (dd, 1H), 6.25 (d, 1H), 5.50 (d, 1H), 5.41 (s, 2H), 4.21 (t, 2H), 3.28 (t, 2H) ppm. MS (ESI) m/z (C17H15ClN4O2S) 375.0 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH:19]=[CH2:20])=[CH:12][N:11]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:9][C:10]1[N:11]=[C:12]2[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH2:19][CH2:20][N:1]2[CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:14][N:15]=1
Reactant: CN1CCC(N)CC1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 200 mg, 1.74 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. for 3 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 0-5% 2M ammonia in MeOH/DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow solid (39 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]([CH3:32])[C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc(NC(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 18 h
Yield: 58.4 %

Procedure:
To a solution of cyclopropanecarboxylic acid {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide (138 mg, 0.33 mmol) in DMF (2 mL) was added at ambient temperature potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.44 mL, 0.40 mmol). After the dark brown solution was stirred for 15 min iodomethane (25 μL, 0.40 mmol) was added and the reaction mixture was stirred for 18 h in a closed flask. It was then extracted with water (20 mL) and ethyl acetate (20 mL). The combined organic layers were then washed with aqueous sodium carbonate (saturated, 20 mL), concentrated, dissolved in ethyl acetate (3 mL) and treated with heptane (3 mL). The resulting suspension was filtered off and washed with ethyl acetate:heptane 1:1 (3 mL) affording the title compound (83 mg, 58%) as a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[O:29])[CH2:22][CH:23]2[C:26]([Cl:28])=[O:27])=[CH:19][CH:18]=1>C(N(CC)CC)C>[ClH:28].[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[O:29])[CH2:22][CH:23]2[C:26]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:27])=[CH:19][CH:18]=1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: COc1ccc2c(c1)C(C(=O)Cl)CC2=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C(=O)N1CCCCC1CN1CCCC1)CC2=O
Yield: 36.5 %

Procedure:
From 1.21 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride. 1.35 g of 6-methoxy-3-oxoindan-1-carbonyl chloride and 2.79 ml of triethylamine. 0.72 g of the title compound was obtained, melting at 210°-228° C. (dec) using a procedure similar to that in Example 2.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:31]N1C(=O)CCC1=O.CN(C)C=O>>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([Cl:31])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (13.9 mg, 0.0343 mmol) and N-chlorosuccinimide (5.33 mg, 0.0399 mmol) in N,N-dimethylformamide (0.3 mL, 4 mmol) was stirred at r.t. for 30 min. It was quenched and stirred with water (4 ml) for 5 min, then filtered, washed with water and dried in vacuo to give 10.1 mg of the title compound as a colourless solid, yield 67%. LC-MS (m/z) 439.4 & 441.6 (3:1, MH+); tR=1.52 (method C). 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.77 (overlapping s, 3H, Me), 1.70-1.92 (overlapping m, 5H), 2.07 (br. m, 1H), 2.17 (s, 3H, Me), 2.67 (m, 1H, CH of Cb), 4.94 (t, J=8.3 Hz, CH—N), 7.03 (br. t, 1H), 7.14 (br. d, J=9.8 Hz, 1H), 7.18 (br. d, J=7.7 Hz, 1H), 7.22 (br., 2H, Ph), 7.35 (br. m, 1H), 7.5 (br. t, 1H, para-H of Ph), 7.55 (br. m, 2H, two meta-H of Ph), 8.68 (br. d, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[N:22]=[N:23][N:24]=[C:2]12
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nnnn3c2n1

Procedure:
A mixture of Example 1B (0.175 g, 0.516 mmol) and sodium azide (0.037 g, 0.568 mmol) in N,N-dimethylformamide (5 mL) was heated at 70° C. for 1 hour. The reaction mixture was diluted with water and brine and extracted with ethyl acetate (2×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (95:5 to 90:10) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=3[I:30])=[N:8]2)=[C:4]([NH2:22])[N:3]=1
Reactant: COc1ccc(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC

Procedure:
A solution of 2-Fluoro-8-(3,4-dimethoxy-benzyl)adenine (50 mg, 0.165 mmol), NIS (74 mg, 0.33 mmol), TFA (18.8 mg, 12.7 L, 0.165 mmol) in acetonitrile (120 L) was stirred at room temperature for 24 h. Following solvent removal, the product (12 mg, 16.9%) was collected through silica gel column purification (CHC13:MeOH:AcOH at 80:1:0.5 to 30:1:0.5). MS m/z 430.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](OB(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)Oc1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cccc(-c2ccccn2)c1

Procedure:
Under an inert gas atmosphere, 2-bromopyridine and 1.2 equivalents of 3-bromophenylboric acid were subjected to the Suzuki coupling (catalyst: tetrakis(triphenylphosphine)palladium(0), base: 2M sodium carbonate aqueous solution, solvent: ethanol, toluene), to obtain 2-(3′-bromophenyl)pyridine represented by the following formula:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]2[C:4]([CH:3]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:6]=2
Reactant: C[Si](C)(C)C#CCCN
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Product: C[Si](C)(C)C#CCCn1cc2ccc(F)cc2n1
Yield: 100 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 4-fluoro-2-nitro-benzaldehyde (180 mg, 1.06 mmol) and 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol). The crude product was purified by by flash chromatography (cyclohexane/AcOEt 4:1) to yield 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.06 mmol).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCO)O2
Yield: 70.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 497 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.98 mmol), 370 mg CDI (2.28 mmol) and 239 mg 5-aminopentanol (2.2 mmol) produced 468 mg of 6-hydroxy-N-(5-hydroxypentyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)=CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 82%), MS (ISP) m/z=411.4 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: C=CCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and allyl chloroformate by using the same method as in Example 107.
Reaction SMILES: [C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH2:29][C:30]1[S:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH2:39])=[CH:32][C:31]=1[CH3:40])[CH3:28]>>[C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8]([NH:39][CH2:38][CH2:37][S:36][CH2:35][C:33]1[S:34][C:30]([CH2:29][N:27]([CH3:26])[CH3:28])=[C:31]([CH3:40])[CH:32]=1)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSC(=C[N+](=O)[O-])NCC(O[SiH](C)C)(c1cccc(C)c1)C(C)(C)C
Reactant: Cc1cc(CSCCN)sc1CN(C)C
Product: Cc1cccc(C(CNC(=C[N+](=O)[O-])NCCSCc2cc(C)c(CN(C)C)s2)(O[SiH](C)C)C(C)(C)C)c1
Yield: 80 %

Procedure:
In the same manner as in Example 6-(2), 3.8 g of 1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)-ethyl]amino}-1-methylthio-2-nitroethene and 2.6 g of 2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamine were reacted and treated to obtain 4.6 g (yield 87%) of oily N-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[NH2:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1
Yield: 77 %

Procedure:
(3S, 4R)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (1.85 g. 5.9 mmole) is hydrogenated with 2 g of 10% palladium on activated carbon in THF (30 ml) and ethyl acetate (30 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, 810 mg of deprotected (3S, 4R)-3-amino-4-phenoxy-azetidin-2-one is obtained.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C>>[N:1]12[P:15]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCNCCNCCN1
Product: C1CN2CCN3CCN(CCN1)P23

Procedure:
1,4,7,10Tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane is prepared in the absence of a solvent by heating 5.0 g of 1,4,7,10-tetraazacyclododecane and 4.7 g of hexamethylphosphorous triamide together at about 75° C for between two and three hours and subliming the crude product at 75° C. at 0.4 mm. The yield is 5.3 g (92%) of product melting at 106°-108° C.