Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>CO>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1
Reactant: Fc1ccccn1
Reactant: OC[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC[C@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Yield: 58.4 %

Procedure:
(S)-Pyrrolidin-3-ylmethanol (9.89 mmol, 1 g), 2-fluoropyridine (29.7 mmol, 2.88 g) and triethylamine (49.4 mmol, 6.89 ml, 5.00 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. The resulting residue was purified by silica chromatography, eluting with DCM—5% MeOH/DCM to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methanol (1.03 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12]C>Br.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: COc1ccc(S(C)(=O)=O)cc1F
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A solution of 2-fluoro-4-methanesulfonyl-1-methoxy-benzene (1.00 g, 4.9 mmol) in a mixture of 48% aqueous HBr (3 mL) and 33% HBr in acetic acid (1.5 mL) was heated at reflux for 20 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered, evaporated and chromatographed, eluting with 30% ethyl acetate/hexanes, to give 2-fluoro-4-methanesulfonyl-phenol (800 mg, 86%) as a white solid. Mass spectrum (APCI) m/z M−H=189.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-tert-butyl-benzenesulfonamide [CAS 608523-94-0] according to general procedure II. Light yellow solid. MS (ISP) 566.2 [(M−H−]; mp 228° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:24]4[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (82 mg, 88%), MS (ISP) m/z=372.4 [(M+H)+], mp 311.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:24]([C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Yield: 85.1 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (3 g, 13 mmol), phenol (1.22 g, 13 mmol), pyridinium p-toluenesulfonate (50 mg) and chloroform (100 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over sodium sulfate, volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a light brown solid which was recrystallised to afford the title compound (3.6 g) as a white solid m.p. 99°-101° C. (from diethyl ether-hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH:16]([CH3:18])[CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)C(=O)OC(C)C
Product: CC(C)OC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared by following General Procedure AO above using isopropanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([O:19][CH3:20])[CH:3]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.CC(O)=O>CO>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)[CH2:14][CH2:15]2)=[O:9])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
A mixture of N-(4,5-dichloro-2-methoxybenzyl)piperidine-4-carboxamide (750 mg, 2.37 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (607 mg, 3.55 mmol), AcOH (1 mL) and MeOH (5 mL) was stirred at reflux for 2 h. To this mixture, NaBH3(CN) (0.74 g, 11.85 mmol) was added and the resulting mixture was stirred at 60° C. for 16 h. The mixture was allowed to cool to room temperature and partitioned between NH4Cl aqueous solution and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (220 mg, 18% yield). ESI-MS m/z: 472.3[M+H]+.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:45][CH2:46][CH2:47][OH:48]>CN(C=O)C.O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH2:45][CH2:46][CH2:47][OH:48])[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: OCCCBr
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCO)S(C)(=O)=O)CC2)n1
Temperature: 20 °C
Reaction time: 168 h
Yield: 49 %

Procedure:
To a mixture of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide (Example 17) (1.95 g, 3.62 mmol) and K2CO3 (6 g, excess) in DMF (20 mL) was added 3-bromo-1-propanol (4 mL, excess). The reaction mixture was stirred at 20° C. for 7 days and diluted with water. The resulting sticky material was extracted into CH2Cl2 (4×30 mL) and dried (Na2SO4). Evaporation of the solvent and the chromatography of the residue on silica, eluting with a gradient of CH2Cl2 and EtOAc (0-20%) followed by CH2Cl2/MeOH (97:3) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-(3-hydroxypropyl)methanesulfonamide (1.04 g, 49%): mp (CH2Cl2/MeOH) 219-221° C.; 1H NMR (DMSO-d6) δ7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.73 (d, J=12.8 Hz, 1H), 4.82 (d, J=12.3 Hz, 1H), 4.44 (t, J=5.1 Hz, 1H), 3.97 (S, 3H), 3.92-3.83 (m, 1H), 3.80-3.79 (m, 4H), 3.69 (m, 4H), 3.40-3.32 (m, 2H), 3.14-2.96 (m, 4H), 3.96 (s, 3H), 1.87-1.80 (m, 2H), 1.74-1.64 (m, 4H); Anal Calcd. for C25H34F2N8O5S: C, 50.33; H, 5.74; N, 18.78. Found: C, 50.2; H, 5.9; N, 18.5%.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[SH:22])[CH2:9][CH3:10].Br[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1>O>[CH2:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[S:22][CH:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[CH2:28][CH2:29]1)[CH2:9][CH3:10]
Reactant: CCCOc1cc(C(F)(F)F)ccc1S
Reactant: FC(F)(F)c1ccc(N2CCC(Br)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(C(F)(F)F)ccc1SC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 60% sodium hydride was added, with chilling on ice, to the DMF (7 ml) solution of the chemical compound (46) (0.62 g), it was warmed to room temperature, and was then stirred for 30 minutes. After the chemical compound (48) (0.74 g) was added to the mixture, it was heated to 100° C., and was then stirred for 1 hour. After the mixture was cooled, it was poured into water, and was then subjected to extraction with ethyl acetate. After its organic layer was washed with water, and was then dried with anhydrous magnesium sulfate, it was filtered, and was then concentrated under reduced pressure. Its residue was purified by column chromatography to produce the chemical compound mentioned in the above title (0.90 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>>[O:23]=[C:14]1[C:15]2[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:18])[N:13]1[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O

Procedure:
tert-Butyl 2-(1,3-dioxoisoindolin-2-yloxy)ethylcarbamate 2E was prepared with quantitative yield from tert-butyl 2-hydroxyethylcarbamate and N-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1. ESI-MS: m/z 329.3 (M+Na)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC/C=C/CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC/C=C/CCOS(=O)(=O)c1ccc(C)cc1
Yield: 99 %

Procedure:
This compound was synthesized as a colorless oil from (E)-hex-3-en-1-ol (130.0 mg, 1.30 mmol), TsCl (322.2 mg, 1.69 mmol), Et3N (196.6 mg, 1.95 mmol), and DMAP (158.8 mg, 1.30 mmol) in 99% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.74 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.50 (dtt, J=15.3, 6.3, 1.3 Hz, 1H), 5.27-5.14 (m, 1H), 4.00 (t, J=6.9 Hz, 2H), 2.43 (s, 3H), 2.36-2.23 (m, 2H), 2.03-1.86 (m, 2H), 0.91 (t, J=7.5 Hz, 3H);
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:21])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a 100 mL flask, 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.2 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.4 mmol) were added. After five drops of N,N-dimethyl formamide was added, a large number of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was evaporated to dryness at reduced pressure. Then toluene (100 mL) was added, and the reaction mixture was concentrated again under vacuum to give the product (0.42 g) as green solid in 100% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][CH:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2cc(Br)ccc12
Product: Clc1nccc2cc(Br)ccc12
Yield: 62 %

Procedure:
A solution of 6-bromo-1-hydroxylisoquinoline (9.205 g, 41.0 mmol) in POCl3 (100 mL) was heated to 100° C. for 4 h. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and the organic layer was washed with 5% NaHCO3, water, brine, dried over MgSO4 and concentrated. The residue was was chromatographed on silica gel eluting with CH2Cl2:hexane (3:7) to give the title compound (6.176 g, 62%). MS (DCI/NH3) m/z 241, 243 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:22][CH2:21][CH2:20][CH2:19][CH:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)=[CH:7][N:6]=1)=[O:4]
Reactant: CN1CCC(CCCN)CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CO
Product: COC(=O)c1cnc(NCCCC2CCN(C)CC2)cn1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 equiv.) and 3-(1-methyl-piperidin-4-yl)-propylamine (1.1 equiv.) in MeOH (0.25 M) heated at 100° C. in a sealed tube for 4 h. The mixture was cooled to rt and concentrated to give a crude product which was purified by FCC.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH2:28](O)[CH3:29]>S(=O)(=O)(O)O.C1C=CC=CC=1>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:28][CH3:29])=[O:2]
Reactant: Cc1ccccc1OCC(O)COc1cccc2oc(C(=O)O)cc(=O)c12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccccc3C)cccc2o1

Procedure:
A mixture of 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-o-cresyloxypropane (10.0 g), ethyl alcohol (5 ml), benzene (100 ml) and concentrated sulphuric acid (5 drops) were heated together under a Dean and Stark trap for 18 hours. After cooling, the solution was washed successively with sodium bicarbonate solution and water. Removal of the benzene afforded a viscous oil nucleated with crystals. Recrystallization of the crude product from aqueous dioxane gave 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-o-cresyloxypropane (8.75 g), m.p. 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:31][CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:21])([F:20])[F:22])=[CH:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Product: C[C@H](Oc1ncc(C(=O)NCc2ccccn2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1 using (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylic acid (example AH) and 2-pyridinemethanamine (CAN 3731-51-9) as starting materials; MS (ESI): 437.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[OH:30])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)C>[C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:30])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Solvent: CC(C)O
Product: O[C@@H]1CNCC[C@H]1CN(Cc1ccccc1)Cc1ccccc1
Yield: 100.9 %

Procedure:
A mixture of intermediate (70) (0.284 mol) in 2-propanol (1000 ml) and a mixture of 6N HCL in 2-propanol (250 ml) was stirred and refluxed for 15 minutes and then cooled. The solvent was evaporated. A 5% aqueous NaOH solution (750 ml) was added. The mixture was extracted three times with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 88.95 g of (trans)-4-[[bis(phenylmethyl)amino]methyl]-3-piperidinol (intermediate 71).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 75 °C
Yield: 61.2 %

Procedure:
To a solution of the 5-bromo-6-(2,4-difluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step E (80 mg, 0.17 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (35 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.50 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (58 mg, 61% yield). MS (M, M+2): 557, 559; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 5.50-5.60 (m, 2H), 6.87-6.94 (m, 2H), 7.54-7.58 (m, 3H), 7.92 (s, 1H), 8.13 (d, J=7.04 Hz, 1H), 8.77 (d, J=4.30, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C[Si]([C:14]([F:17])([F:16])[F:15])(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:14]([F:17])([F:16])[F:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (27.0 g, 146.5 mmol) and trimethylsilyl-trifluoromethane (25.0 g, 175.8 mmol) in tetrahydrofuran (300 ml) was added drop-wise tetrabutylammonium fluoride (1 M in tetrahydrofuran, 5 ml, 5 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 2 hours. Further tetrabutylammonium fluoride hydrate (49.0 g, 175.8 mmol) was added and the mixture was stirred for 30 minutes. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (200 ml) and washed with hydrochloric acid (2N aqueous solution) (4×100 ml). The organic layer was separated, washed with Na2CO3 (10% aqueous solution) (50 ml), dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford the crude title compound as a yellow oil (45.0 g, ˜100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[C:7](=[O:12])[CH:6]=2
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: Oc1cc2cnc(Br)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1

Procedure:
The alkylation of 7-bromo-3-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>C(O)C>[OH:4][CH2:3][CH2:2][S:1][C:10]1[C:5](=[O:12])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: OCCS
Solvent: CCO
Product: O=C1C=CC(=O)C(SCCO)=C1
Reaction time: 0.01 h

Procedure:
2-Mercaptoethanol (25.9 ml, 0.368 mole) is added in a single amount to a suspension of p-benzoquinone (80 g, 0.736 mole) in absolute ethanol (500 ml), with stirring and while bubbling nitrogen through the suspension. The temperature rises from 22° C. to 45° C. within 30 seconds and the mixture becomes a homogeneous red-brown. At the end of 15 minutes, a precipitate appears. The mixture is left to stand with stirring for 2 hours and filtered through a no. 4 frit. The orange-red precipitate is washed with 3×50 ml of cold ethanol and dried. Orange crystals are obtained
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1.Cl.[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl>C(O)C>[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1
Reactant: Nc1ccccc1CCl
Reactant: Sc1nc2c([nH]1)CCCC2
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1CSc1nc2c([nH]1)CCCC2
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a suspension of 1.5 g (purity 75%, 7.3 mmol) of 2-mercapto-4,5,6,7-tetrahydro-1H-benzimidazole in 15 ml of ethanol was added 1.3 g (7.3 mmol) of 2-aminobenzyl chloride hydrochloride, and the mixture was stirred for 2 hrs. at room temperature. Ethanol was distilled off under reduced pressure at room temperature. The residue was made alkaline by addition of saturated aqueous sodium hydrogencarbonate and then extracted with 40 ml of chloroform. The chloroform portion was washed with 10 ml of 0.2N NaOH and then with saturated aqueous sodium chloride. The washed chloroform portion was dried over anhydrous sodium sulfate and placed under reduced pressure to distill off the solvent. The residue was purified by silica gel column chromatography using chloroform-methanol to give 1.35 g of the desired compound as a pale yellow oil, yield 71.4%.