Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1C=CC(S(O)=O)=[CH:22][C:18]=1C(O)=O.C1(CN)CC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH2:13][CH:22]2[CH2:18][CH2:17]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: NCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Yield: 81 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and cyclopropylmethylamine and obtained in 81% yield. MS (m/e): 288.0 (MH−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:27])[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (5 g, 14.7 mmol) in N,N-dimethylformamide (30 ml) was added 60% sodium hydride (710 mg, 17.7 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added methyl iodide (5 ml, 80 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.76 g, 91%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-(trifluoromethyl)phenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (55 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=370.0 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:43])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]3[NH:23][C:24](=[O:43])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:35]=[N:36][C:37]([CH:40]6[CH2:41][CH2:42]6)=[CH:38][CH:39]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2cc(OCC3CC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (5-cyclopropylmethoxy-2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M178) (240 mg, 0.39 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (74 mg, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH:27][CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11]([NH:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C

Procedure:
The compound is prepared from 650 mg (2.3 mmol) of methyl 2-[(tert-butoxycarbonyl)amino]-6-chloropyridine-3-carboxylate (Example 118A) and 363 mg (2.3 mmol) of N-Boc-ethylenediamine as described in Example 114A. 500 mg (50% of theory) of the product are obtained as a solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:30])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([F:30])[CH2:28][CH2:29]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@@H](N)C[C@H]1CC[C@H](F)CC1)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)-propyl(methyl)carbamate (200 mg, 0.47 mmol) in TFA/CH2Cl2 (15 mL, v/v 20%) was stirred for 1 h at rt, then quenched by addition of sat'd aq NaHCO3 solution until gas evolution ceased. The mixture was extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to obtain benzyl (S)-2-amino-3-(trans-4-fluorocyclohexyl)propyl(methyl)carbamate (140 mg, yield 93%). 1HNMR (CDCl3, 400 MHz): δ 1.42 (m, 4H), 1.64 (m, 4H), 2.98 (d, 3H), 3.21 (m, 1H), 3.50 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CN1CCOCC1.[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48].C(O)C(N)(CO)CO>ClCCl>[OH:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][N:14]([C:47]([C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[F:44])=[O:48])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C(NOC1CCCCO1)C1(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CCNCC1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccccc1F)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 [L) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:16]
Reactant: CCO
Reactant: Cc1cccnc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncccc1C
Temperature: -20 °C

Procedure:
3-Methyl-pyridine-2-carboxylic acid (1 g, 7.29 mmol) was dissolved in EtOH (50 mL) and cooled to −20° C. Thionyl chloride (1.1 mL, 14.6 mmol) was added, and the resulting white suspension was refluxed for 5 h, then concentrated to dryness. Water (10 mL) was added and solid Na2CO3 was added to neutralize the solution. The resulting mixture was extracted with ether. The organic layer was dried over MgSO4, and the solvent was removed by distillation to give 1.25 g of the title compound as an oil. 1H NMR (CDCl3, 200 MHz): δ=8.54 (d, 1H, J=3.9 Hz), 7.59 (d, 1H, J=7.8 Hz), 7.26-7.40 (m, 1H), 4.45 (q, 2H, J=7.0 Hz), 2.59 (s, 3H), 1.45 (t, 3H, J=7.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.O>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
The mixture of p-nitrophenylhydrazine (12) (15.0 g, 97.9 mmol) and cyclohexanone (10.15 ml, 97.9 mmol) in acetic acid (45 ml) was heated and stirred for 20 minutes at 60° C. To the reaction mixture was added conc. hydrochloric acid (15 ml) and the resulting mixture was heated for 1.5 h at reflux. To the reaction mixture was added water (50 ml), heated for 10 minutes at reflux, and allowed to cool to room temperature. The precipitated crystal was filtered off, washed with water, and recrystallized from ethanol-water to give 6-nitrotetrahydrocarbazole (13) (17.0 g; yield 80%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)CSc3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.405 mmol) was reacted with N-(2-azidoethyl)-2-(phenylthio)acetamide (0.096 g, 0.405 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-(phenylthio)acetamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), δ 7.19 (m, 5H), δ 7.13 (s, 1H), δ 6.43 (s, 1H), δ 6.13 (bs, 2H), δ 4.29 (s, 2H), δ 3.68 (s, 2H), δ 3.57 (s, 2H), δ 2.56 (s, 2H), δ 2.35 (s, 2H), δ 1.52 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 187.8, 172.0, 169.1, 162.4, 156.9, 135.0, 129.5, 128.3, 126.8, 121.8, 85.00, 49.4, 39.9, 37.4, 29.4, 28.9, 28.4, 28.2, 27.6, 25.6 ppm; HRMS (ESI) calcd for C25H35N7O3S (M+) 513.2522. found 513.2522, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-(phenylthio)acetamide hydrochloride (0.133 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), δ 7.30 (s, 4H), δ 7.19 (s, 1H), δ 6.58 (s, 1H), δ 4.66 (s, 2H), δ 3.76 (s, 2H), δ 3.64 (s, 2H), δ 2.84 (s, 2H), δ 2.34 (s, 2H), δ 1.73 (s, 2H), δ 1.64 (s, 2H), δ 1.26 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 170.9, 159.3, 158.9, 147.2, 135.6, 128.1, 128.9, 127.6, 126.6, 108.7, 108.6, 52.-, 39.1, 37.5, 37.2, 36.6, 36.1, 30.8, 28.1, 27.9, 27.7, 24.2, 23.7, 23.6 ppm; HRMS (ESI) calcd for C20H27N7OS (M+) 413.1998. found 413.1991.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:15]=[CH:14]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 4-fluorobenzyl bromide and 5-bromoindole in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a white solid; mp: 57-58° C. Mass spectrum (APCI, [M+H]+) m/z 304. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (d, 1H J=1.8 Hz), 7.55 (d, 1H, J=3.2 Hz), 7.43 (d, 1H, J=8.9 Hz), 7.24-7.19 (m, 3H), 7.12 (t, 2H, J=8.9 Hz), 6.47 (d, 1H, J=3.6 Hz), 5.40 (s, 2H), and 2.22 ppm (s, 3H). Elemental Analysis for C15H11BrFN: Calculated: C, 59.23; H, 3.65; N, 4.61. Found: C, 59.00; H, 3.55; N, 4.58.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.288 g, 1.14 mmol) was treated with 1.0 M KOtBu in THF (1.10 mL, 1.10 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added as a solid, followed by the addition of DMF (3.3 mL), and the resultant mixture was stirred at ambient temperature for 40 hours. The crude reaction mixture was chromatographed on SiO2 eluting with a gradient of (2% NH4OH in isopropanol)/methylene chloride. The desired product was isolated as a pale yellow solid (196 mg). MS APCI (+) m/z 498.2 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[CH2:8][CH3:9]
Reactant: CCc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CCCCO
Product: CCc1c(N)ncnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a mixture of 4,6-Dichloro-5-ethylpyrimidine (22.5 g, 0.12 mol) in 1-butanol (70 mL) in a 1L glass pressure tube was added aqueous ammonia (26%, 150 mL) at RT. The vessel was sealed and heated to 100° C. for 12 h. The reaction mixture was cooled to RT, the resulted solid was filtered, washed with water (50 mL) and dried under vacuum to afford the titled compound (11.0 g, 55%) as white solid. LCMS: Mass found (M+, 158.0). 1H NMR (400 MHz, CDCl3) 8.02 (s, 1H), 7.10 (bs, 2H), 2.57-2.50 (m, 2H), 1.03-0.99 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[C:14](O)=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].II.CO>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][OH:15])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 699 mg (18.48 mmol) sodium borohydride in 20 mL dry THF under nitrogen, was added 1.15 g (5.74 mmol) (S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester and the reaction was cooled to 0° C., 1.72 g (6.78 mmol) iodine in 10 mL dry THF was added dropwise over 30 minutes, the reaction mixture was allowed to warm to room temperature, and was heated under reflux for 19 hours. The mixture was cooled to room temperature and 25 mL MeOH was added dropwise over 15 minutes. After evaporation of the solvent, 30 mL KOH (1 M) was added and the mixture was stirred at room temperature for 2 hours. The aqueous phase was extracted with DCM (2×75 mL) and the combined organic layers were washed with saturated brine (3×50 mL), then dried over MgSO4. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-(2-fluorophenyl)ethanol (5.5 g) and imidazole (8.0 g) in DMF (50 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (6.52 g), then removed from the cooling bath and stirred at room temperature for 3.5 hours. The solution was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford the subtitled compound as a colourless oil. Yield 9.9 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]([O-])=O.[Na+].[OH-].[Na+].[ClH:37]>O>[ClH:37].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:19][CH:20]=2)[NH:18][N:31]=[C:21]3[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Reaction time: 0.67 h
Yield: 64 %

Procedure:
A stirred solution of 4-(4-benzylpiperazin-1-yl)-2-[(phenylsulfonyl)methyl]-aniline (0.371 g, 0.88 mmol) in 4.0 M aqueous hydrochloric acid is cooled in an ice bath, treated dropwise with NaNO2 (91 mg, 1.32 mmol) in water, stirred for 40 min, treated with 2.5 M aqueous NaOH to pH ˜14 and filtered. The filtercake is dissolved in CH2Cl2, and chromatographed (silica gel, ethyl acetate as eluent) to afford the free indazole of the title product as a yellow solid (276 mg, 64%). The solid is dissolved in a mixture of ethanol and CH2Cl2, treated with 4.0 M HCl in dioxane, and concentrated in vacuo to give a solid residue. The residue is triturated with ethyl acetate to afford the title product as an off-white solid, 278 mg (57% yield), mp 177-180° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)CC(=O)NCCN
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCCNC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
Crude N-(2-aminoethyl)acetoacetamide hydrobromide (50 g, 0.18 mole) was dissolved in N,N-dimethylformamide (500 ml). Triethylamine (78 g, 0.4 mole) and methacryloyl chloride (19 g, 0.18 mole) were added simultaneously at 0° C. The reaction solution was then stirred at 0° C. for 1 hour and at 20° C. for 20 hours. The resulting solution was filtered, the solvent removed, and the residue dissolved in chloroform (500 ml). The solution was then washed with 10% hydrochloric acid (200 ml), then water (200 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed. The residue was recrystallized from ethanol/ether (1:1). The resulting compound had a m.p. of 86°-90° C. The yield was 25%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)[CH3:2]
Reactant: CCOC(=O)Nc1ccc2c(c1)CCC2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(1-Oxo-indan-5-yl)-carbamic acid ethyl ester (0.94 g, 4.3 mmol) was dissolved in 20 ml of concentrated sulphuric acid and cooled to 0° C. using an ice-bath. Potassium nitrate (477 mg, 4.7 mmol) was added in small portions. After complete addition, the mixture was stirred for 3 hours at 0° C. and then poured onto crushed ice. The yellow precipitate was filtered off, washed thoroughly with water and dried in vacuo to give a yellow solid product (0.85, 75%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[F:1])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (5.05 g, 0.0223 mol) and 4-bromoaniline (3.83 g, 0.0223 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (4.26 mL, 0.0245 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue was partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.74 (s, 1H), 7.90 (m, 2H), 7.74 (d, 1H), 7.68 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([CH:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13].CCOCC>ClCCl>[CH2:12]([CH:14]([CH2:19][CH2:20][CH:21]=[O:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13]
Reactant: CCC(CCCO)C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CCC=O)C(=O)OC
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 59323.1 %

Procedure:
To 50.46 g (0.234 mmol) of pyridinium chlorochromate, under argon, was added 100 mL of dichloromethane followed, with rapid stirring, by 25.0 g (0.156 mmol) of methyl 2-ethyl-5-hydroxypentanoate in 20 mL of dichloromethane. After stirring at 20° C. for 2.5 h, 15 g of silica gel was added followed by 200 mL of ether. Filtration through a 3.5×40 cm silica gel column (60-200 mesh), eluting with ether and concentration at 40° C. under vacuum gave an oil, which was redissolved in 100 mL of dichloromethane. Washing with 3×100 mL of cold 1N HCl, 3×100 mL of satd. NaHCO3, drying over MgSO4, filtration, concentration at 40° C. and distillation gave methyl 2-ethyl-5-oxopentanoate 14.64 g (59%) product, b.p 104°-105° C. (16 mm Hg).