Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]1[N:24]3[O:25][CH2:26][CH2:27][CH2:28][C:23]3=[N:22][C:15]=1[CH:16]=[N:17]2>ClCCl>[N:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]1[N:24]3[O:25][CH2:26][CH2:27][CH2:28][C:23]3=[N:22][C:15]=1[CH:16]=[N+:17]2[O-:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2c(c1)ncc1nc3n(c12)OCCC3
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ncccc21)OCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Solid 3-chloroperoxybenzoic acid (0.26 g of approximately 77% pure material, 1.1 mmol) was added to a solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine (0.13 g, 0.6 mmol) in dichloromethane (15 mL). The reaction was stirred at room temperature for 1 hour and then washed with saturated aqueous sodium carbonate (10 mL). The aqueous fraction was extracted 5 times with 25 mL portions of dichloromethane. The combined organic fractions were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine 5-oxide (0.13 g).
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[C:7]([OH:15])(=[O:14])[C@H:8]([CH2:10][C:11]([OH:13])=[O:12])[OH:9]>>[C:7]([O-:15])(=[O:14])[C@H:8]([CH2:10][C:11]([O-:13])=[O:12])[OH:9].[K+:5].[K+:5]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 2 h
Yield: 230.4 %

Procedure:
46.2 g (0.334 mole) of potassium carbonate are dissolved in 500 ml of an aqueous L-malic acid solution[L-malic acid content: 75.9 g (0.566 mole)/500 ml]. The solution (pH 4.4) is concentrated at 60° C. under reduced pressure to make the total weight thereof about 170 g. The concentrated solution is cooled to 10° C., and the mixture obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 2 hours. After stirring, the mixture had a pH of 5.8. The crystalline precipitates are collected by filtration. 80.9 g of monopotassium potassium L-malate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>CCOC(C)=O>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of methyl 2-bromo-5-chlorobenzoate (10 g, 40 mmol) in concentrated H2SO4 (48 ml, 910 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (3.35 ml, 52 mmol) and concentrated H2SO4 (3.4 ml, 64 mmol) was added dropwise to the reaction mixture at 0° C. over 30 minutes. The yellow reaction mixture was stirred at 0° C. for 1.5 hours before being poured onto ice. EtOAc (150 ml) was added and the phases were separated. The organic phase was washed with deionized water (3×50 ml) followed by brine (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 12.0 g (60%) of the title compound material as a pale yellow oil which solidified upon standing. This material contained 40% of the 6-nitro isomer. This material was used without further purification. LC-MS 91%, m/z=no ionisation, 1H NMR (500 MHz, Chloroform-d) δ 7.86 (1H, d, J=2.52 Hz), 7.77 (1H, d, J=2.52 Hz), 3.99 (3H, s).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1O[S:5]([CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=[O:7])=[O:6].[N:31]1([CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N:31]1([CH2:36][CH2:37][CH:38]2[CH2:39][CH2:40][N:41]([S:5]([CH2:8][CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]3)(=[O:6])=[O:7])[CH2:42][CH2:43]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)C1
Reactant: C1CCN(CCC2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CCS(=O)(=O)N2CCC(CCN3CCCC3)CC2)C1

Procedure:
tert-Butyl 3-(2-(perfluorophenoxysulfonyl)ethyl)piperidine-1-carboxylate (0.5 g, 1.09 mmol) and 4-(2-pyrrolidinoethyl)piperidine (0.4 g, 2.18 mmol) were dissolved in tetrahydrofuran (10 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 ml, 3.27 mmol) was added under an inert gas and the mixture was refluxed for 2 h. Ethyl acetate and saturated sodium bicarbonate solution (20 ml of each) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% aq) (300:100:1). Yield: 0.32 g (64%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=O)[CH2:13][CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CCO.O>[OH:18][N:17]=[C:12]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]c3c(c2c1)CCC3=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CCC3=NO
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A stirred solution of 1,2-cyclopentadione mono-4-methoxyphenylhydrazone (6.0 g) in 100 ml of 10% aqueous H2SO4 was heated on a steam bath for 4 hours and thereafter allowed to cool to room temperature and filtered to give 1,4-dihydro 7-methoxy-cyclopent[b]indol-3(2H)-one as a solid. To the indole (2.6 g) in 25 ml of 95% EtOH was added hydroxylamine hydrochloride (1.7 g) in 15 ml water followed by sodium acetate (2.1 g) in 15 ml water. The mixture was heated at reflux for 2.5 hours and allowed to stand overnight. The EtOH was removed in vacuo and the solid material which formed was collected and purified by flash chromatography to give 0.8 g of a mixture of oxime isomers.
Reaction SMILES: [S:1]1(=[O:7])C=C[C:3](=[O:6])[NH:2]1.S(Cl)(Cl)(=O)=O.[CH2:13]([Cl:16])[CH2:14][Cl:15]>>[Cl:15][CH:14]1[CH:13]([Cl:16])[S:1](=[O:7])[NH:2][C:3]1=[O:6]
Reactant: O=C1C=CS(=O)N1
Reactant: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=C1NS(=O)C(Cl)C1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2g. (0.02 mole) of 4-isothiazolin-3-one 1-oxide in 80 ml. ethylene dichloride (EDC) is added 2.4g. (0.02 mole) of sulfuryl chloride. The mixture is stirred at room temperature overnight. The white solid which forms is filtered, washed with EDC and air dried to yield 2.0g. (52%) of product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:18]=[C:15]([NH:14][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[CH:5]=1)[C:2]([F:19])([F:20])[F:1])/[CH:16]=[CH:17]/[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:31]([F:32])([F:34])[F:33])[CH:23]=1
Reactant: O=C(O)c1ccc(I)cc1C(F)(F)F
Reactant: C=CC(=O)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(/C=C/c1ccc(C(=O)O)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Under argon, first 3.34 g (7.90 mmol) of N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-acrylamide from Example 2. Stage 1, and then 2.49 g (7.90 mmol) of 4-iodo-2-(trifluoromethyl)benzoic acid (commercially available, CAS Registry Number: 954815-11-3), 0.206 g (7.90 mmol) of triphenylphosphine, 88.4 mg (0.39 nmol) of palladium(II) acetate and 13.5 g (133 mmol) of triethylamine were initially charged in 67 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 100° C., for 5 hours. After addition of water, the solution was extracted with ethyl acetate, and then the organic phase was washed three times with saturated sodium chloride solution and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Br[CH2:22][CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:22][CH2:23][CH2:24][OH:25])[CH:10]=3
Reactant: O=c1ccn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: OCCCBr
Product: O=c1ccn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 36 %

Procedure:
According to Example 34, the compound (145 mg) produced in Example 58 was reacted with 3-bromopropanol (65 μl) to obtain the title compound (62 mg; 36%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2[O:14]1.C(=O)([O-])[O-].[Ca+2]>CC(C)=O>[CH3:12][C:4]([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:22][C:17]1[CH:18]=[CH:19][C:20]2[O:21][CH2:13][O:14][C:15]=2[CH:16]=1
Reactant: CC(=CCBr)CCC(C)=C(C)C
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC(C)=C(C)C

Procedure:
26 g of 1-bromo-3,6,7-trimethyl-2,6-octadiene, 13 g of 3,4-methylenedioxy-phenol [sesamol] and 20.75 g of finely pulverized calcium carbonate were refluxed for 68 hours in 100 ml of acetone. After reflux the reaction mixture was filtered and the acetone solution was evaporated. By chromatography on Kieselgel with hexane-diethylether (4:1 parts by volume) and distillation under vacuum there was obtained pure 3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2,6-octadiene, b.p. 114°-117°C/0.002 mmHg; nD20 = 1.5352.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]([C:22]3[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=3)[C:18](=[O:31])[CH:17]=2)[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]([C:22]3[S:23][C:24]([C:28]([NH:7][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=4)=[O:29])=[C:25]([CH3:27])[N:26]=3)[C:18](=[O:31])[CH:17]=2)[CH2:12][CH2:11]1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobenzylamine in place of benzylamine to react with 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 30% yield: mp 172-174° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 8.32-8.27 (m, 2H), 7.05-7.00 (m, 2H), 6.17-6.08 (m, 2H), 5.97 (t, J=2.5 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.87-0.93 (m, 1H), 0.54-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.9, 163.9, 162.2, 160.6, 153.6, 152.4, 133.6, 131.3, 129.6, 122.0, 115.8, 104.2, 96.6, 69.1, 43.3, 33.6, 17.3, 7.5, 4.2; MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[CH:10]=[CH:11]2)[CH3:29]
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCOS(C)(=O)=O)ccc32)cc1
Reactant: CCNCC
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCN(CC)CC)ccc32)cc1

Procedure:
In analogy to example 5.5, Methanesulfonic acid 5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester and diethylamine were converted to yield Diethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine as yellow oil, MS: 355 (MH+).
Reaction SMILES: O1C2C=CC=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[ClH:12].N[N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]([CH3:25])[O:17][CH2:16][CH2:15]1.Cl.N1CCC(=O)CC1>>[ClH:12].[CH3:25][CH:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:4]4[CH2:3][NH:2][CH2:11][CH2:6][C:5]=4[N:14]([C:20]=23)[CH2:15][CH2:16][O:17]1
Reactant: C1=Cc2ccccc2ON=C1
Reactant: CC1OCCN(N)c2ccccc21
Agent: Cl
Agent: O=C1CCNCC1
Product: CC1OCCn2c3c(c4cccc1c42)CNCC3

Procedure:
According to the procedure described in Example 1, the appropriate benzoxazepine is converted to 1-amino-1,2,3,5-tetrahydro- 5-methyl-4,1-benzoxazepine hydrochloride, m.p. 198°-200°, which is reacted with 4-piperidone hydrochloride to yield the title compound, m.p. 285°-286° (dec.).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.CN1CCOCC1>CN1CCCC1=O>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cc3)CC4)nc(N)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (17 mg, 0.039 mmol), 4-fluorobenzonitrile (7.1 mg, 0.058 mmol) and 4-methylmorpholine (13 μL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL) was heated at 180° C. overnight. After cooling, the mixture was filtered, diluted with methanol, and purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=426.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9](=[O:25])[C@H:10]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:15]([O:14][C:12]([NH:11][C@@H:10]([CH2:19][C:20]1[N:24]=[CH:23][N:22]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH:21]=1)[C:9]([O:8][CH3:7])=[O:25])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)CCBr
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@H](Cc1cn(CCC(C)C)cn1)NC(=O)OC(C)(C)C

Procedure:
1-Bromo-3-methylbutane (4.44 ml, 37.2 mmol) was added to a mixture of Nα-Boc-L-histidine methyl ester (5.0 g, 18.6 mmol) and sodium carbonate (4.0 g, 37.2 mmol) in acetonitrile (80 ml), and the mixture was heated under reflux for 18 hours. The cooled mixture was concentrated under reduced pressure. The residue was suspended in water and the suspension was basified using sodium carbonate then extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of hexane:ethyl acetate (100:0 to 5:95) to afford the title compound as a colourless oil, 2.8 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.90 (d, 6H), 1.40 (s, 9H), 1.50 (m, 1H), 1.60 (m, 2H), 2.96-3.06 (m, 2H), 3.62 (s, 3H), 3.82 (t, 2H), 4.50 (m, 1H), 5.85 (m, 1H), 6.62 (s, 1H), 7.32 (s, 1H). LRMS: m/z (ES+) 340 [MH+]. [α]D=−2.3 (c=0.22, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:13][Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OS(C)(=O)=O)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of the product from Step A (10.38 g, 39.2 mmol) and N-bromosuccinimide (8.61 g, 48.4 mmol) in 80 mL of carbontetrachloride was added 2,2′-azobisisobutyronitrile (0.89 g, 5.4 mmol), and the reaction was heated at reflux overnight under argon. The solution was cooled to room temperature, concentrated in vacuo, slurried with 30% EtOAc/hexane solution, and filtered. The filtrate was washed with saturated aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a 2:1 mixture of the titled product and a tribromide as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=[O:6])[CH3:3].[O:7]=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[S:20][C:21]([NH:29]C(N)=O)=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[CH:10]=[CH:9]1>>[CH2:2]([NH:4][C:5]([NH:29][C:21]1[S:20][C:12]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:7])[CH:9]=[CH:10][C:11]=2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])[CH3:3]
Reactant: CCN=C=O
Reactant: NC(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: Cl
Product: CCNC(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1

Procedure:
The title compound was prepared from the HCl salt of the compound of Example 81 and ethyl isocyanate following the method described for the compound of Example 97 to give the product as a solid (24 mg). δH (DMSO-d6) 8.59 (1H,s), 7.8–7.4 (11H, m), 6.67 (1H, t, J 5 Hz), 6.38 (1H, d, J 10 Hz), 3.1–2.9 (2H, m), 0.97 (3H, t, J 7 Hz). LCMS (ES+) 390 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])[NH2:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:55]3[CH:56]=[CH:57][C:52]([C:49](=[O:51])[NH2:50])=[CH:53][CH:54]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C(N)=O)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-carbamoylphenylboronic acid to give 34 on a 0.1 mmol scale via General Procedure H (62 mg, 49%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.82 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.39 (s, 2H, CH2), 5.03 (s, 2H, CH2), 5.34 (s, 2H, CH2), 5.91 (s, 1H, NH2), 6.44 (s, 1H, NH), 6.65 (s, 1H, CH2), 6.68 (d, 1H, CH), 7.19 (d, J=6.0 Hz, 2H, CH), 7.24-7.35 (m, 4H, CH), 7.38-7.41 (m, 2H, CH), 7.44-7.50 (m, 6H, CH), 7.53 (d, J=4.8 Hz, 1H, CH), 7.59 (s, 2H, CH), 7.61 (s, 2H, CH), 7.64 (d, J=5.4 Hz, 2H, CH), 7.68 (d, J=5.4 Hz, 2H, CH), 7.83 (d, J=6.3 Hz, 1H, CH), 7.89 (d, J=6.0 Hz, 2H, CH); δC (100 MHz, CDCl3) 21.3, 35.9, 51.3, 52.7, 66.9, 70.6, 113.9, 119.9, 120.8, 126.8, 126.9, 127.1, 127.3, 127.9, 128.1, 128.1, 128.3, 128.4, 128.4, 129.4, 131.8, 131.8, 131.8, 131.9, 132.0, 132.8, 133.0, 135.1, 135.5, 135.6, 136.3, 139.1, 143.2, 143.8, 144.8, 158.7, 165.2, 167.0, 168.8; LRMS (ES+) calcd for [C45H41N3O7S+H] 768.27 found 768.27.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[CH:7][N:8]=1.[ClH:19]>CO.O1CCOCC1.C(OCC)(=O)C>[ClH:19].[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH2:11])[CH3:10])=[CH:7][N:8]=1
Reactant: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CSc1ncc(C(C)N)nn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 3) (13.3 g, 49 mmol) in methanol (100 mL) was added 4N HCl in dioxane (50 mL). After stirring for 30 minutes the volatiles were removed under reduced pressure to provide a colorless oil. The oil was taken up in ethyl acetate, and the volatiles again removed under reduced pressure to give 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine hydrochloride (10.1 g) as a white solid. MS m/z 171 (M+1). A portion of the white solid (90 mg) was slurried in ethyl acetate and washed with saturated sodium bicarbonate solution causing the solid to dissolve. The volatiles were removed under reduced pressure to give 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine (68 mg) as a foam. MS m/z 171 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1.C(O)CCC>C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][N:23]([C:2]3[CH:11]=[C:10]([Cl:12])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=3)[CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1
Reactant: Clc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: Brc1ccc2c(c1)CCCNC2
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Clc1ccc2nc(N3CCCc4cc(Br)ccc4C3)cc(Cl)c2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (291 mg, 1.29 mmol) and n-butanol (3 mL) was heated with stirring in a 10 mL microwave process vial for 1 hour at 160° C. under microwave irradiation. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), and then washed with water (10 mL). The organic layer was dried over sodium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel to give 222 mg of product as a white solid (yield was 41%). MS obsd. (ESI+) [(M+H)+] 421.