Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cl
Yield: 99.5 %

Procedure:
To a solution of 4-chloro-3-methoxybenzoic acid (4.88 g, 26.2 mmol) in THF (50 mL) was added borane-THF complex (52 mL 1M solution in THF, 52 mmol) via addition funnel over 10 min. The reaction mixture was refluxed for 2 hr, cooled, extracted with EtOAc, washed with water, 5% Na2CO3 and brine, dried and concentrated in vacuo to give (4-chloro-3-methoxyphenyl)methan-1-ol (4.5 g, 99%). ES-MS (M+H−H2O)+=155, 157 (Cl).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1nnco1
Product: O=C(Nc1nnco1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 239-240° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from [1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride. The [1,3,4]oxadiazol-2-ylamine, white solid, MS: m/e=85 (M+) used in the above reaction was prepared in accordance with the general method of example 44b from formic acid hydrazide and cyanogen bromide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([Cl:23])[CH:16]=1.[C:24](O)(=[O:27])[CH2:25][SH:26]>C(#N)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[S:26][CH2:25][C:24](=[O:27])[NH:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[C:5]2=3)=[C:17]([Cl:23])[CH:16]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: Cn1nc(-c2ccccn2)cc1N
Reactant: O=C(O)CS
Solvent: CC#N
Product: Cn1nc(-c2ccccn2)c2c1NC(=O)CSC2c1ccc(Br)cc1Cl
Temperature: 150 °C
Yield: 70.3 %

Procedure:
A mixture of 1-methyl-3-(2-pyridyl)pyrazol-5-amine (1.6 g, 9.2 mmol), 4-bromo-2-chloro-benzaldehyde (2.0 g, 9.1 mmol, Apollo Scientific), and thioglycolic acid (3.4 g, 37 mmol) in acetonitrile (20 mL) was heated, in a sealed microwave vessel, for about 20 min, at about 150° C., in a microwave. After cooling to rt the precipitated solid was collected by filtration and washed with acetonitrile (4 mL) to afford 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (2.86 g, 6.4 mmol, 70%), which was used as such. 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.10 (1H, d, J=12 Hz); 3.43 (1H, d, J=12 Hz); 3.86 (3H, s); 6.68 (1H, s); 6.93 (1H, d, J=8 Hz); 7.15 (1H, m); 7.28 (1H, dd, J=2 Hz, 8 Hz); 7.65 (1H, d, J=2 Hz); 7.70 (1H, dd, J=2 Hz, 8 Hz), 7.78 (1H, d, J=8 Hz); 8.34 (1H, d, J=4 Hz); 10.2 (1H, s).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[O:8]=O>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=O
Reactant: C1=CC2CCC1C2
Product: O=C1CC2CCC1C2
Product: O=CC1=CCCCC1
Yield: 70 %
Yield: 30 %

Procedure:
7.1 g norbornene and 1 atm O2 were passed over 100 mg of this material at 280° C. for 2 hours, yielding in a partial conversion 99 mg norbornanone (relative yield 70%) and 43 mg cyclohexene carboxaldehyde (relative yield 30%) with a turnover frequency of 160 moles total product per mole Rh per hr.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:34])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.CN(C)C=[O:38]>>[OH2:38].[ClH:34].[Cl:34][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:29][C:28]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: Cl
Product: Cc1cc(Nc2ccc(Cl)c(C(F)(F)F)c2)c2c(ccc3nc[nH]c32)n1
Product: O

Procedure:
A stirred mixture of the compound of Example I, C. (22 g. 0.1 mole) and 5-amino-2-chlorobenzotrifluoride (20 g. 0.1 mole) in 200 ml. of dimethylformamide, was refluxed for 6 hours. The reaction solution was stripped in vacuo to give 35 g. (82%) of tan product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38](O)=[O:39])=[CH:30][C:29]=1[Cl:41].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.C(#N)C>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:6][CH2:7]2)=[O:39])=[CH:30][C:29]=1[Cl:41]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCCO2
Reactant: COc1cc(C(=O)CCCN2CCC(O)CC2)cc(OC)c1OC
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(C(=O)CCCN2CCC(OC(=O)c3cc(Cl)c(N)c4c3OCCC4)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
4-(4-hydroxy-1-piperidinyl)-1-(3,4,5-trimethoxyphenyl)-1-butanone (3.3 g) was added to a solution of sodium hydride (0.4 g) in tetrahydrofuran (100 ml) (solution I) under a N2 flow. A mixture of 5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (2.14 g) and 1,1'-carbonylbis-1H-imidazole (2 g) in acetonitril (100 ml) was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (100 ml) (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated. The residue was diluted with water and extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /hexane/(CH3OH/NH3) 50/42/3). The desired fractions were collected and the solvent was evaporated. The residue (2.3 g) was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2 /CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried, yielding 0.93 g of 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl 5-amino-6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylate (17%); mp. 112.7° C. (compound 8).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.O.[NH2:32][NH2:33]>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:32][NH2:33])=[O:30])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Yield: 63 %

Procedure:
A mixture of 3.2 parts of phenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate, 50 parts of hydrazine hydrate and 100 parts of 1,4-dioxane is stirred and refluxed for 3 hours. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from N,N-dimethylformamide, yielding 1.7 parts (63%) of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide; mp. +300° C.
Reaction SMILES: CN(C)CCN(C)C.[CH:9]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[CH2:10].C([Li])CCC.[C:21]([C:25]1[CH:38]=[CH:37][CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])([CH3:24])([CH3:23])[CH3:22].C(=O)=O>CCCCCC.O.O1CCCC1>[C:21]([C:25]1[CH:38]=[CH:37][CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:12]1[N:11]([CH:9]=[CH2:10])[CH:15]=[CH:14][N:13]=1)[OH:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: C=Cn1ccnc1
Reactant: CC(C)(C)c1ccccc1C(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cn1ccnc1C(O)(c1ccccc1)c1ccccc1C(C)(C)C
Temperature: -60 °C
Reaction time: 2 h

Procedure:
To a solution of 28.8 g. (0.25 mol) of N,N,N',N'-tetramethylethylenediamine and 17.6 g. (0.19 mol) of 1-vinylimidazole in 300 ml. of anhydrous tetrahydrofuran, 14 ml. (0.25 mol) of 20% butyllithium in n-hexane were added drop-wise with stirring at -60° C., and under a nitrogen atmosphere over the course of one hour. Stirring was continued for 2 hours under the same conditions, after which a solution of 48 g. (0.20 mol) of 2-tert.-butylbenzophenone in 300 ml. of anhydrous tetrahydrofuran was added drop-wise. The reaction mixture was stirred for 3.5 hours, after which the cooling means was removed and stirring was continued overnight under the nitrogen atmosphere. The lithium complex obtained was then decomposed with 15 ml. of water and a large excess of solid carbon dioxide. The precipitate was filtered off, the filtrate was dried over sodium sulphate and the solvent was distilled off. The solid residue was twice crystallised from ethyl acetate to which a small amount of ethanol had been added. α-(o-tert.-Butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol was obtained. Melting point 152°-153° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.OC1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NC(CCNC)NC
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of meta-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.81 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 g of 1-(3-nitrobenzoyl)pyrrolidine, the characteristics of which are as follows:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:18][C:19](=[O:41])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:40])[CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17].[Br:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br-:42].[Cl:8][C:9]1[CH:10]=[C:11]([NH:18][C:19](=[O:41])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N+:25]([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])([CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[CH3:40])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17]
Reactant: COc1ccc(CCCBr)cc1
Reactant: CCOc1ccc(NC(=O)NCCCCN(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CCOc1ccc(NC(=O)NCCCC[N+](C)(CCCc2ccc(OC)cc2)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1Cl
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture comprising 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [2-({4-[3-(3-chloro-4-ethoxy-phenyl)-ureido]-butyl}-methyl-amino)-ethyl]-amide trifluoroacetate (435 mg, 0.85 mmol), 1-(3-bromo-propyl)-4-methoxy-benzene (1.83 g, 7.99 mmol) and sodium carbonate (270 mg, 2.54 mmol) in acetone (8 mL) is heated at reflux for 11 days. After cooling to RT, the mixture is filtered and concentrated in vacuo. DCM is added and the precipitated solid is collected by filtration. The solid is crystallised from ethanol to afford the title compound. M+ 661. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (1H, s), 8.29 (1H, t), 7.63 (2H, br), 7.62 (1H, d), 7.15 (1H, dd), 7.10 (2H, d), 6.99 (1H, d), 6.93 (2H, br), 6.81 (2H, d), 6.23 (1H, t), 4.01 (2H, q), 3.71 (3H, s), 3.61-3.56 (2H, m), 3.39-3.29 (4H, m), 3.08 (2H, q), 3.03 (3H, s), 2.49 (2H, t), 2.00-1.91 (2H, m), 1.72-1.64 (2H, m), 1.42 (2H, quint), 1.32 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([C@H:9]([CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]([OH:13])=O)[CH3:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][CH2:69][C:70]1[CH:75]=[N:74][CH:73]=[CH:72][N:71]=1>CCOC(C)=O.CN(C=O)C>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([NH:17][C:16](=[O:28])[O:15][CH2:14][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=2[Cl:1])=[O:29])[CH2:10][C:11](=[O:13])[NH:68][CH2:69][C:70]2[CH:75]=[N:74][CH:73]=[CH:72][N:71]=2)[N:19]=1
Reactant: NCc1cnccn1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)NCc1cnccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a mixture of the crude (S)-3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoic acid (1.47 mmol) and DMF (5 mL) were added DIEA (0.512 mL, 2.94 mmol) and HBTU (0.667 g, 1.76 m mol). The resulting mixture was stirred at RT for 10 min and 2-aminomethylpyrazine (0.192 g, 1.76 mmol) was added. The resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (100 mL). The organic layer was washed by NaHCO3 solution and concentrated. The resulting residue was purified on silica gel column (DCM/MeOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-oxo-4-(pyrazin-2-ylmethylamino)butyl isoquinolin-3-ylcarbamate (0.65 g, 76.2%). LRMS (M+H+) m/z 580.1
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:21][C:22](Br)=[O:23].Cl>C(Cl)Cl>[C:17]([CH:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:22](=[O:23])[CH3:21])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)C1CCC(c2ccccc2)CC1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Referring to Scheme 2-7 to a suspension of AlCl3 (1.58 g, 12 mmol) in DCM (30 mL) at −78° C. was added 1-(4-phenylcyclohexyl)ethanone (A1′) (1 g in DCM, 5.0 mmol), and bromoacetyl bromide (0.65 mL, 7.5 mmol) dropwise over 10 min. The mixture was stirred to rt for 15 min and heated at 40-50° C. for 3 h, cooled to rt and poured into a mixture of ice and HCl (1N). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were concentrated on rotovap and purified silica gel column chromatography (Hexanes/EtOAc=8/2 (v/v)) to give the desired trans-isomer A2′ (1 g, 62% yield) along with a small amount of cis-isomer.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH3:10].Cl.[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[N:20]=[C:19]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH3:10])[CH2:37][CH2:38]2)[CH2:13][CH2:14][CH2:15]1
Reactant: COc1c(N)ncnc1Cl
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-Chloro-5-methoxy-pyrimidin-4-ylamine (45.00 mg; 0.28 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine hydrochloride (4) (148.13 mg; 0.28 mmol; 1.00 eq.), and Cs2CO3 (367.53 mg; 1.13 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2 days, purified by HPLC collected title compound 17 mg. LC-MS: (M+1=503, obsd.=503).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])C[C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OC(C1C=C(O)C2CCOC=2C=1)=O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:8]2[CH2:14][CH2:12][O:13][C:9]=2[CH:10]=1)=[O:4])[CH3:26]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: CCOC(=O)c1cc(O)c2c(c1)OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cc2c(c(Oc3ccc(S(C)(=O)=O)cc3)c1)CCO2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (285 mg, 1.64 mmol), Cs2CO3 (997 mg, 3.06 mmol), and 4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid ethyl ester (8b) (315 mg, 1.51 mmol). Purification by column chromatography eluting with 10-20% EtOAC in hexanes gave a pale yellow oil (199 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.90-7.97 (m, 2 H) 7.34 (d, J=4.29 Hz, 1 H) 7.24-7.29 (m, 1 H) 7.07-7.13 (m, 2 H) 4.67 (m, 2 H) 4.32-4.39 (m, 2 H) 3.09-3.14 (m, 2 H) 3.06-3.09 (m, 3 H) 1.34-1.42 (m, 3 H); LCMS for C18H18O6S m/z 385.00 (M+Na)+.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:46]([OH:48])=[O:47])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:45])[CH2:26][CH2:27][CH:28]([P:37]([CH2:42][CH:43]=[CH2:44])([CH2:39][CH:40]=[CH2:41])=[O:38])[P:29]([CH2:34][CH:35]=[CH2:36])([CH2:31][CH:32]=[CH2:33])=[O:30])=O)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:31]([P:29]([CH:28]([P:37]([CH2:39][CH:40]=[CH2:41])([CH2:42][CH:43]=[CH2:44])=[O:38])[CH2:27][CH2:26][C:25]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:46]([OH:48])=[O:47])[NH2:18])=[O:45])([CH2:34][CH:35]=[CH2:36])=[O:30])[CH:32]=[CH2:33]
Reactant: C=CCP(=O)(CC=C)C(CCC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)P(=O)(CC=C)CC=C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C=CCP(=O)(CC=C)C(CCC(=O)NCCCC[C@H](N)C(=O)O)P(=O)(CC=C)CC=C
Yield: 85.6 %

Procedure:
A solution of 90 (502 mg, 0.616 mmol) in piperidine/DMF (0.05:1, 5 mL) was stirred at room temperature for 18 hr. After diluting with ethyl acetate (40 mL) the organic layer was washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (methanol in ethyl acetate, 5% over 5 column volumes then 5 to 30% over 10 column volumes) using a Biotage Horizon™ apparatus resulting in the colourless liquid 91 (249 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 1.39-1.74 (m, 6H), 1.45 (s, 9H), 2.21-2.35 (m, 2H), 2.51 (t, J=7.4, 2H), 2.55 (tt, J=6.9, 23.9, 1H), 3.19-3.25 (m, 2H), 3.29 (dd, J=5.2, 7.6, 1H), 4.58-4.63 (m, 8H), 5.25 (dq, J=1.3, 10.3, 4H), 5.38 (dq, J=1.4, 17.1, 4H), 5.90-6.00 (m, 4H), 6.14 (bd, J=4.9, 1H): 31P (162 MHz, CDCl3) δ 24.67 (s, 2P).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:29]([O:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([Br:16])=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:26]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2cc(Br)ccc2c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (955.0 mg, 3.4 mmol), K2CO3 (1.2 g, 8.5 mmol), KI (56.2 mg, 0.3 mmol) and BnBr (0.6 mL, 4.7 mmol) in DMF (17 mL) was stirred at 60° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2) to give the title compound in 1.1 g. MS: (+) m/z 372.20 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].O>C(Cl)Cl>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.05 g, 0.187 mmol) in DCM (1 mL) cooled to 0° C. were added triethylamine (0.038 g, 0.374 mmol) and isopropylsulfonylchloride (0.029 g, 0.206 mmol). The resulting suspension was stirred at 0° C. for 4 h and then allowed to warm up to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with DCM, poured into H2O (5 mL) and extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.023 g, 33%) as a white foam. MS: 374.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Br-:10].[K+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1.CCOCC>[Br:10][CH2:9][CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCCCC1CO1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: OCCCCCC(O)CBr

Procedure:
A mixture of 5 (120 mg, 0.9 mmol) in acetic acid-tetrahydrofuran (2 mL-0.4 mL) was treated with 0.3 mL of saturated aqueous potassium bromide solution at room temperature over 67 hours. It was then diluted with ether and poured into saturated aqueous sodium bicarbonate. The separated organic layer was washed with saturated sodium thiosulfite, saturated sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent gave 127 mg of 7-bromo-6-hydroxy-1-heptanol (4).