Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Br[CH2:3][CH:4]=[C:5]([CH3:18])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14].[CH3:19][OH:20]>>[CH3:19][O:20][CH2:3][CH:4]=[C:5]([CH3:18])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14]
Reactant: CC(=CCBr)CCC=C(C)CCC(C)=C(C)C
Reactant: CO
Agent: [Na]
Product: COCC=C(C)CCC=C(C)CCC(C)=C(C)C

Procedure:
To a solution containing 8.6 g. of sodium dissolved in 172 ml. of absolute methanol, then was added dropwise over a period of 30 minutes, 111 g. of 1-bromo-3,7,10,11-tetramethyl-2,6,10-dodecatriene. The reaction mixture was refluxed for 16 hours. After reflux, the reaction mixture was dried under vacuum and poured onto ice water. The resulting mixture was exhaustively extracted with petroleum ether (b.p. 40°-45°C.). The combined petroleum ether extracts were washed neutral with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on Kieselgel with hexane/diethylether (95:5 parts by volume) and distillation, there was obtained 1-methoxy-3,7,10,11-tetramethyl-2,6,10-dodecatriene, b.p. 87°-88°C./0.02 mmHg; nD20 = 1.4826
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)C(C)C)C>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[N:24][C:19]([C:18]([F:17])([F:30])[F:29])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a suspension of 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (37 mg, 0.12 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (26 mg, 0.12 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 70 mg, 0.13 mmol) in CH3CN (1.0 mL) was added (i-Pr)2EtN (32 mg, 0.25 mmol) at 20° C. The reaction mixture was stirred at 20° C. under argon for 15 h, then concentrated in vacuo. The residue was dissolved in EtOAc (15 mL). The organic solution was successively washed with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μ C18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with EtOAc to afford 54 mg (92%) of the title compound as a white solid. LC/MS (method B): retention time 1.91 min, [M+H]+=487.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1C(C)=NC=C(C)N=1.Cl[C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[N:23]=1
Reactant: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCc1cnc(CC)c(Cl)n1
Product: CCc1cnc(CC)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Following the procedure for the preparation of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine but 3-chloro-2,5-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.19, 1.35, 2.65, 2.88, 7.29, 7.39, 7.54, 8.47; 13C NMR (CDCl3) δ 13.52, 14.48, 28.03, 28.97, 128.01, 130.22, 132.07, 134.61, 135.77, 137.02, 143.22, 150.44, 154.57, 155.84; MS (ESI+) for C14H14Cl2N2 m/z 282.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH:19]=2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)c2)CC1
Product: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)c2)CC1
Yield: 74.2 %

Procedure:
Following general procedure F, {6-bromo-4-[3-(2-(4-methylpiperazin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.165 mmol) to afford the desired product (47 mg, 74%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.25 (s, 1H), 7.89 (s, 2H), 7.69 (s, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.13-6.94 (m, 4H), 2.97-2.84 (m, 1H), 2.82-2.72 (m, 2H), 2.66-2.51 (m, 10H), 2.43 (s, 3H), 1.32-1.06 (m, 4H). ESI MS m/z 575 [C32H32C12N4O2+H]+; HPLC 95.1% (AUC), tR=10.37 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH3:33])=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH:32]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[CH3:33])=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(OC(=O)Cl)c1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OC(C)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 1-(4-chlorophenyl)ethyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: Brc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4-Bromo-1-iodobenzene (5 g, 17.7 mmol) in tetrahydrofuran (20 mL) at −40° C. was treated dropwise with isopropyl magnesium chloride (2 M solution in tetrahydrofuran, 23 mmol, 11.5 mL) and following addition was stirred 1 hour. Cyclohexanone (1.5 mL, 14.75 mmol) in tetrahydrofuran (5 mL) was added and the solution was allowed to slowly warm to room temperature over 3 hours. Saturated aqueous ammonium chloride solution was added and the mixture was then diluted with ethyl acetate. The aqueous and organic layers were separated and the organic layer was washed with water (1×) and brine (1×). The combined aqueous layers were extracted with ethyl acetate (3×10 mL), the combined organic layers were dried over magnesium sulfate, were filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (20:1 hexanes-ethyl acetate) to afford 3 g (67% yield) of 1-(4-bromo-phenyl)-cyclohexanol. 13C NMR (100 MHz, CDCl3) □ 148.8, 131.4, 126.8, 120.8, 73.2, 38.9, 25.6, 22.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH:7]=[N:8][C@H:9]([C:17]([O-:19])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:10]([C@H:9]1[C:17](=[O:19])[O:18][C@@H:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=2)[N:8]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C=N[C@@H](Cc2ccccc2)C(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](Cc3ccccc3)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-4-Benzyl-N-benzyloxycarbonyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (13) was prepared from sodium N-(para-methoxybenzylidene)-(L)-phenylalaninate (3.05 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a white solid after crystallisation from diethyl ether (2.87 g, 69%): [α]D20 +50.1 (c 1.0, CHCl3); mp 85° C.; IR (KBr): 1795, 1700 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.49-7.08 (m, 14H), 6.04 (s, 1H), 4.92 (d, J=12 Hz, 1H), 4.83 (d, J=12 Hz, 1H), 4.19 (dd, J=4, 6 Hz, 1H), 3.39 (s, 3H), 3.25 (dd, J=6, 14 Hz, 1H), 3.08 (dd, J=4, 14 Hz, 1H); 13C NMR (50.3 MHz, CDCl3): δ 171.4, 160.3, 151.5, 135.3, 129.2, 128.8, 128.5, 128.2, 127.3, 113.4, 89.3, 67.8, 58.4, 55.3, 34.5; LRMS (EI): 418 (MH+). Anal. Calcd for C25H23NO5 : C, 71.93; H, 5.55; N, 3.35. Found: C, 72.22; H, 5.36; N, 3.28.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([Cl:27])[N:19]=1>C(#N)C>[Cl:27][C:20]1[N:19]=[C:18]([NH:16][C:15]2[C:10]([O:9][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: COc1ncccc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ncccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 14.1 %

Procedure:
Triethylamine (6.5 mL, 46.6 mmol) was added to a solution of 2-methoxypyridin-3-amine (1.0 g, 8.1 mmol) and 2,6-dichloro-3-nitropyridine (1.62 g, 8.4 mmol) in acetonitrile (30 mL) and the resulting mixture was stirred at ambient temperature for 5 days and then at 50° C. for 24 h. The precipitate formed was filtered, washed with acetonitrile and dried in vacuo. The solid was then treated with tetrahydrofuran, filtered, washed with more tetrahydrofuran and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (0.32 g, 11%) as an orange solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH:22]=[CH:21][CH:20]=[N:19][C:17]=2[N:18]=1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH:22]=[CH:21][CH:20]=[N:19][C:17]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)NCc1nc2ncccc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
Benzyl isocyanate was added to a solution of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (example 24.1) in pyridine; the reaction mixture was kept at r.t. overnight. The volatiles were evaporated and the title compound was isolated from the reaction mixture by reversed-phase, preparative HPLC. MS: m/e=308.4 [M−H−].
Reaction SMILES: [C:1]([CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[O:26][CH:28]2[C:27]([O:31][CH3:32])=[O:30])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=O
Reactant: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using petroleum ether/ethyl acetate =7:3 as eluant.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[CH3:36][NH2:37]>O1CCCC1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:37][CH3:36])=[CH:13][CH:12]=2)[C:8]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:9]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCCl)ccc2n1Cc1cccc(OC)c1
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCNC)ccc2n1Cc1cccc(OC)c1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A reaction mixture of ethyl 5-(2-chloroethoxy)-1-(3-methoxybenzyl)-3-(4-methoxyphenyl)-1H-indole-2-carboxylate (Example 152, 290 mg, 0.588 mmol) and methylamine in tetrahydrofuran (2 M, 40 ml) was sealed in a stainless steel vessel (100 ml, bomb) at 0° C. Then it was heated and stirred at 120° C. for 3 days in a oil bath. Oil bath was removed and the bomb was allowed to cooled to room temperature before opened. The reaction solution was transferred to an round-bottomed flask and solvent was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N NaOH. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by flash column (silica gel, hexane: ethyl acetate=1:1 to ethyl acetate:2M NH3/ methanol =9:1). 214 mg desired product was obtained as a light yellow oil in 75%. MS (M+H)=489.2, Rf=0.28 (ethyl acetate:2M NH3/methanol=4:1).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:17]1[C:16](=[C:25]3[C:20](=[CH:19][CH:18]=1)[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12]2(=[O:13])=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccc(C(F)(F)F)cc21
Yield: 7.9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinolin-8-yl-5-trifluoromethyl-benzenesulfonamide (Intermediate 300) (330 mg, 0.9 mmol), t-butyl nitrite (0.16 ml, 1.3 mmol), AcOH (3.3 ml) and THF (3.3 ml) gave the title compound (25 mg, 7%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
12.2 g of 1,3-benzodioxole were placed in 75 ml of glacial acetic acid in a 250 ml sulfonation flask equipped with stirrer, thermometer and dropping funnel and then nitrated at 15°-25° C. by the dropwise addition of 9 ml of nitric acid(d=1.4) in 30 ml of glacial acetic acid. The mixture was stirred at room temperature overnight, the precipitated crystals were removed by filtration under suction, washed with water and recrystallized from alcohol. There were obtained 14.0 g of 5-nitro-1,3-benzodioxole of melting point 149°-150° C. and from the mother liquor an additional 2.0 g of melting point 148°-149° C. Total yield: 90.6% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:18][CH:19]=1)#[N:24]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dinitro-benzoyl chloride (0.69 g, 3.0 mmol) in 2 mL toluene was added to a stirred mixture of 2-amino-5-cyanopyridine (0.357 g, 3.0 mmol) and 5 mL pyridine. After stirring overnight at ambient temperature the mixture was concentrated i.vac. The residue was taken up in ethyl acetate and 5% NaHCO3 (aq). The organic layer was washed with water and brine, separated, dried and concentrated i.vac. The residue was purified by chromatography on silica gel (eluent gradient: dichloromethane/ethanol=100:0->100:2).
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:5][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(CN2CCC(N(C(=O)[O-])C(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl1-[(4-methoxyphenyl)methyl]-4-piperidinylcarbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ml. of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50% sodium hydroxide. Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25](N)=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C@H:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCC(N)=O)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@H](CCCO)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 96° C., [α]D20=−97.1° (c=1.0723 in chloroform) and MS: m/e=378.2 (M+H+)]was prepared in accordance with the general method of example 44 from (2S,5R)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester [see example 59: colorless oil, [α]D20=−96.4° (c=1.0992 in chloroform) and MS: m/e=406.1 (M+H+)].
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br.Br[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21])[CH3:8]
Reactant: O=C1c2ccncc2CCC1Br
Reactant: CCOC(=O)CC#N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)C1CCc2cnccc2C1=O
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred, cold (4° C.) solution of ethyl cyanoacetate (52.2 mmol) and 6-bromo-7,8-dihydro-6H-isoquinolin-5-one 8B (6.5 mmol) in DMF (10 mL), DIEA (19.5 mmol) was added. The mixture was brought to rt and stirred for 4 h. Solvent was removed and the residue, dissolved in DCM, was repeatedly washed with water. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (DCM/MeOH 98:2) provided the title compound in 95% yield. ESI (+) MS: m/z 259 (MH+). 1H NMR: 1.15-1.32 (m, 3H), 1.98-2.44 (m, 2H), 3.59-3.82 (m, 3H), 4.20-4.28 (m, 2H), 4.70 (s, 1H), 7.67-7.73 (m, 1H), 8.64-8.68 (m, 1H), 8.75-8.78 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1(C)C=CC=CC=1>[F:19][C:3]1[C:2]([B:25]([OH:30])[OH:26])=[CH:7][C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COCc2cnc(F)c(Br)c2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COCc2cnc(F)c(B(O)O)c2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine (1.615 g, 4.952 mmol) was dissolved in PhMe (25.0 mL) and the reaction flask was cooled under nitrogen in a dry ice/acetone bath. Then, n-butyllithium solution (Fluka, Buchs, Switzerland, 1.6 M in hexane, 3.7 mL, 5.9 mmol) was added via syringe, turning the solution yellow. The reaction was stirred at −78° C. for 45 minutes and then triisopropyl borate (Alfa Aesar, Ward Hill, Mass. 98+%, 1.7 mL, 7.2 mmol) was added via syringe. The reaction was allowed to slowly warm up to room temperature, and after 90 minutes, the dry ice/acetone bath was removed. After another 25 minutes, the reaction was quenched with water and diluted with 10:1 DCM/MeOH. The biphasic solution was treated with 5 N HCl to lower the pH of the aqueous phase from 9 to about 4, and the aqueous phase extracted with 10:1 DCM/MeOH. The organic extracts were concentrated and dried under high vacuum in water bath (about 45° C.-60° C.), and then the solid was washed with Et2O and dried again under high vacuum at room temperature over the weekend to afford 2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-ylboronic acid (1.389 g, 68% purity, 66% yield). MS (ESI pos. ion) m/z 292 (M+H)+.
Reaction SMILES: C1(C[C:8]2[N:12](CCCO)[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[N:9]=2)C=CC=CC=1.S(Cl)(Cl)=O>ClC(Cl)Cl>[NH:9]1[C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[N:12]=[CH:8]1
Reactant: OCCCn1c(Cc2ccccc2)nc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: c1ccc2[nH]cnc2c1
Reaction time: 4 h

Procedure:
To a stirred mixture of 40 parts of 2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 30 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is boiled in water. The solution is filtered over hyflo and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(3-chloropropyl)-2-phenylmethyl)-1H-benzimidazole; mp. 112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:8][C:9]#[N:10].[K+]>C(O)(=O)C.O>[C:2]1([NH:1][C:9]([NH2:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of aniline (2.51 g, 27 mmol) dissolved in glacial acetic acid (14 mL) and water (28 mL) was slowly added a solution of potassium cyanate (4.4 g, 54 mmol) dissolved in water (35 mL). The mixture stirred for 2 h at RT, filtered, washed with water and dried under reduced pressure to yield phenylurea as a white solid (1.85 g, 50% yield). 1H NMR (DMSO-d6): δ 8.47 (s, 1H), 7.38 (dd, J=8.4 Hz, 0.9 Hz, 2H), 7.2 (t, J=7.6 Hz, 2H), 6.88 (t, J=7.6 Hz, 1H), 5.81 (brs, 2H); MS (ESI) m/z: 137 (M+H+).