Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].Br.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([O:16][CH:28]3[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH2:27]3)[C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)c1nc2cc(O)c([N+](=O)[O-])cc2[nH]1
Agent: Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2cc([N+](=O)[O-])c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 2-isopropyl-6-hydroxy-5-nitrobenzimidazole and the HBr addition product (15 g), N-tert-butoxycarbonyl-4-hydroxypiperidine (17.7 g), PPh3 (23.1 g), and THF (150 mL) at room temperature was added DEAD (14 mL). After 4 hours, the solvent was removed in vacuo and the product recovered from the crude using chromatography (3% methanol/methylene chloride) to yield 2-isopropyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-nitrobenzimidazole (16.5 g).
Reaction SMILES: [I:1]Cl.C[Si](C)(C)[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[I:1][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1
Reactant: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc([Si](C)(C)C)ccc5-6)ccc3-4)cc21
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc(I)ccc5-6)ccc3-4)cc21
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
ICl (1.0 M in methylene chloride, 2.80 ml, 2.80 mmol) is added dropwise to a solution of 2-trimethylsilyl-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (13a) (2.45 g, 2.80 mmol) in CCl4 (15 ml) at 0° C. After stirring for 30 min, the reaction mixture is poured into a Na2CO3 aqueous solution (5 wt %) with vigorous stirring until discoloration for extraction with methylene chloride. The organic extracts are washed with brine before dried over MgSO4. Upon evaporating off the solvent, the residue is washed with ethanol to yield 2-iodo-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (14a) (2.36 g, 91%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:49][S:50](Cl)(=[O:52])=[O:51].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:37][CH2:38][N:39]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:40][CH2:41]2)[CH3:35])=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.448 g, 0.805 mmol) in CH2Cl2 (4 mL) at −20° C. was treated with NEt3 (1.122 mL, 8.05 mmol) followed by methanesulfonyl chloride (0.190 mL, 2.414 mmol). The mixture stirred at −20° C. for 30 minutes and then 1 M NaOH (aq.) and CH2Cl2 were added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 75% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.317 g, 0.499 mmol, 62.1% yield) as a white foam. m/z (ESI, +ve) 635.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=9.00 Hz, 1H); 8.18 (s, 1H); 7.17 (d, J=7.63 Hz, 4H); 6.83-6.89 (m, 5H); 4.74 (br. s., 4H); 3.80 (s, 6H); 3.65 (m, 1H); 3.18-3.30 (m, 4H); 2.77 (s, 3H); 2.64 (s, 5H); 2.50-2.58 (m, 2H); 1.44 (d, J=6.65 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10](OC)=[O:11])[N:7]=[N:6]1.[NH3:19]>>[CH:16]1[CH:15]=[C:14]([F:18])[C:3]([CH2:4][N:5]2[N:6]=[N:7][C:8]([C:10]([NH2:19])=[O:11])=[CH:9]2)=[C:2]([F:1])[CH:17]=1
Reactant: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Reactant: N
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
reacting methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV with ammonia to obtain rufinamide of formula I.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][CH2:17][CH:16]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:15]2=[O:28]>C1COCC1>[CH2:1]([C:15]1([OH:28])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[O:18][CH2:17][CH:16]1[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.4 ml (52.8 mmol) of benzylmagnesium chloride under nitrogen atmosphere were cooled to 0° C. with an ice bath and 3.5 g (13.2 mmol) ethyl 6-methoxy-4-oxochroman-3-ylcarbamate dissolved in 100 ml dry THF were slowly added. The mixture was stirred at 0° C. for 1 h. The cooling bath was removed and saturated ammonium chloride solution was added. Water was added until a clear solution was obtained. The phases were separated and the organic phase was washed with saturated ammonium chloride solution, dried over MgSO4, and concentrated in vacuo to give 6.87 g (9.1 mmol, quant.) of crude material.
Reaction SMILES: [S:1]([N:11]([C:18]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:21])[CH2:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:13]([CH:12]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])([OH:21])[C:19]2[C:18](=[CH:32][CH:31]=[C:30]([Cl:33])[CH:29]=2)[N:11]1[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)N2c3ccc(Cl)cc3C(O)(c3ccccc3Cl)C2C(=O)N(C)C)cc1
Yield: 12.7 %

Procedure:
1.5 g of the compound prepared in step B are refluxed in DCM for 24 hours in the presence of 900 mg of DBU. The mixture is chromatographed on a silica column using a DCM/AcOEt mixture (95/5, v/v) as the eluent. 190 mg of the expected product are obtained after recrystallization from isopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][NH2:18])[CH3:16].Cl>CO>[CH2:15]([O:17][N:18]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:16]
Reactant: CCON
Reactant: COC(=O)CC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CCON=C(CC(=O)OC)c1ccc(O)cc1
Temperature: 65 °C

Procedure:
A mixture of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (1 g) and EtONH2.HCl (600 mg) in methanol (10 mL) was heated at 65° C. for 2 h. Methanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue. The aqueous solution was extracted with ethyl acetate (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a colorless oil, which was used directly in Step B. HPLC retention time: 1.51 min (method A). MS (ESI) (M+H)+ 238.09.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([OH:8])=[C:10]([F:19])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(O)c(F)c1
Yield: 0.1 %

Procedure:
To a solution of 2-(benzyloxy)-1,3-difluoro-5-nitrobenzene (5.3 g, 20 mol) in ethanol (100 mL) was added 10% palladium on activated carbon (1.5 g). The mixture was hydrogenated (1 atm) at RT overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-amino-2,6-difluorophenol (2.9 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (brs, 1H), 6.19 (d, J=10.8 Hz, 2H), 5.01 (s, 2H).
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[C:13]1([C:12]2[C:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][NH:9][N:8]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Yield: 54.4 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)propenoate (300 mg), 5% palladium-carbon (600 mg), formic acid (3 ml), and ethanol (10 ml) was refluxed for 2 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (120 mg, yield: 55%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[N+:22]([C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]3)[CH2:16]1)[CH2:10]2)=[O:6])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(N2CCNCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 118.8 %

Procedure:
A mixture of 3-chloro-2-nitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (2.80 g, Example 1a) and piperazine-1-carboxylic acid, tert-butyl ester (7.47 g) in dry dimethyl sulfoxide (10 ml) was heated at 120° C. under a nitrogen atmosphere for 24 h. The cooled reaction mixture was diluted with water and extracted thrice with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a solid. Purification by chromatography over silica gel, eluting with iso-hexane/ethyl acetate (2:1) gave the subtitle compound as a solid (3.8 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazalidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]C2C=CC(C=C3SC(=O)NC3=O)=CC=2[N+]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COc2ccc(C=C3SC(=O)NC3=O)cc2[N+](=O)[O-])CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CO)CCCCC1
Temperature: 80 °C

Procedure:
General Procedure C for compounds 7a-m: A mixture of compound 3 (0.5 mmol), compounds 6a-m (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in 3 mL DMF. The solution was heated to 80° C. for 4 hr. the solution was poured into water, extracted with ethyl acetate (10 ml * 3), and concentrated. The residue was purified by chromatography.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a like manner as described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-tert-butylphenylboronic acid (302 mg, 1.70 mmol) were coupled to yield 2-(4-tert-butyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 150 mg (42%), as a white solid. mp 243-244° C.; 1H NMR (300 MHz, d6-DMSO) δ 1.33 (s, 9H), 3.05 (m, 2H), 3.38 (m, 2H), 7.20 (app t, 1H, J=7.8 Hz), 7.57 (m, 5H), 7.67 (dd, 1H, J=7.2, 0.6 Hz), 8.07 (brt, 1H), 11.51 (br s, 1H); HRMS (FAB, MH+) Calcd for C21H23N2O: 319.1810, Found: 319.1813; Anal. (C21H22N2O.0.3 H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O.CCOCC>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:11][CH2:12][Br:42])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(COCc1ccccc1)COCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCC(COCc1ccccc1)COCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4-benzyloxy-3-benzyloxymethylbutan-1-ol (41.75 g, 139 mmol) in 150 ml of dry dichloromethane was cooled in ice-water bath. Triphenylphosphine (42.0 g, 160 mmol) was added with stirring and then N-bromosuccinimide (26.0 g, 146 mmol) in portions during 15 min. After 1 h at room temperature ether (400 ml) was added and the precipitated triphenylphosphine oxide filtered off. The solution was concentrated in vacuum to a small volume, and more ether was added to extract the product from precipitated triphenylphosphine oxide. Finally, this extraction-precipitation step was repeated with light petroleum to give, after evaporation, 33.55 g (66%) of crude title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:17]([NH:20][C:29](=[O:30])[CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1ccccc1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenyl-propanoyl chloride, gave 5-formyl-6-methoxy-N-(3-phenyl-propanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[CH:14](N(C(C)C)CC)(C)C.IC>CC#N>[I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6]([S:12][CH3:14])=[N:5][C:4](=[O:13])[CH:3]=1
Reactant: COCCn1c(I)cc(=O)[nH]c1=S
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: COCCn1c(I)cc(=O)nc1SC
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a stirring solution of 6-iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (9.00 g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL, 28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, and concentrated in vacuo. The residue was partitioned ortioned between CH2Cl2 (200 mL) and 1N aqueous HCl (100 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by hot trituration with CH2Cl2/heptane to give the title compound (4.05 g, 43%) as a cream colored solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:21])[CH:12]=[C:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.II.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:11](=[O:21])[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:20]1
Reactant: O=C(C=C(S)c1ccccc1)Nc1nc2ccccc2s1
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)sn1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A mixture of 0.250 g (0.800 mmol) N-(2-benzothiazolyl)-3-mercapto-3-phenylpropenamide and 10 mL methylene chloride was stirred at room temperature. Added was 0.203 g (0.800 mmol) iodine dissolved in 10 mL methylene chloride and the mixture stirred 5 mins. Added next was 0.5 mL (excess) triethylamine and the mixture stirred for one hour. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water. The organic layer was dried, filtered and solvent was evaporated. The resulting solid was recrystallized from absolute ethanol to provide 0.090 g (0.290 mmol, 36%) N-(2-benzothiazolyl)-5-phenyl-4-isothiazolin-3-one as a very pale, yellow solid, mp=201°-202° C. NMR (CDCl3 /TMS): 6.6 (s, 1H)7.3-7.95 (m, 9H). IR (Nujol): 1680. High resolution mass spectrum: Calculated; 311.031282. Measured; 311.030775. Anal. calcd. for C16H10N2OS2 : C 61.91, H 3.25, N 9.03, S 20.66; Found C 61.82, H 3.14, N 8.97, S 20.55.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH2:21])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 50 °C
Yield: 61.5 %

Procedure:
7-Nitro-3,4-dihydro-2(1H)-naphthalenone (200 mg, 1.1 mmol) was combined with ammonium acetate (807 mg, 10.5 mmol), sodium cyanoborohydride (86 mg, 1.4 mmol) and MeOH (5 mL) and heated to 50° C. for 15 h. The reaction was cooled and concentrated under vacuum and the residue was partitioned between EtOAc and water. The organic layer was washed with 5% aqueous potassium carbonate, brine and dried over Na2SO4. The crude was concentrated under vacuum and purified by silica gel flash column chromatography (0-100% (90% DCM/9% MeOH/1% NH4OH)/DCM). Purification provided 130 mg (65%) of the desired amine as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.89 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 3.06-2.88 (m, 3H), 2.84-2.72 (m, 1H), 2.54-2.44 (m, 2H), 1.81 (d, J=35.2 Hz, 2H), 1.51-1.42 (m, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[N:47]1[CH2:52][CH2:51][C:50]2[C:53]3[CH2:59][CH2:58][CH2:57][CH2:56][C:54]=3[S:55][C:49]=2[C:48]1=[O:60])(=[O:29])[CH3:28]>>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[C:48](=[O:60])[C:49]3[S:55][C:54]4[CH2:56][CH2:57][CH2:58][CH2:59][C:53]=4[C:50]=3[CH2:51][CH2:52]2)=[CH:34][CH:35]=[CH:36][C:37]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][O:25][CH2:26]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C4COC4)CC3)cc2)c1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C5COC5)CC4)cc3)n2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 68 %

Procedure:
Following Example 136e, 5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one 214b and (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a afforded 305a in 68% yield. LCMS: (M+H)+ 694
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[C:4]([F:14])[CH:3]=1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:16]#[N:15])=[CH:18][CH:19]=2)=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(Br)cc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F

Procedure:
(RS)-(4-Bromo-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow gum.