Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:40]=[CH:39][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:38]=[CH:37][C:29]5[C:30]([O:33][CH2:34][O:35][CH3:36])=[N:31][O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:41])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:48]([O:54][CH2:55]Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50].O>CN(C)C=O.C(OCC)(=O)C>[C:48]([O:54][CH2:55][O:22][C:21](=[O:23])[CH2:20][CH2:19][C:17]1[CH:18]=[C:13]([C:11](=[O:12])[C:10]2[CH:39]=[CH:40][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][C:9]=2[OH:41])[CH:14]=[CH:15][C:16]=1[O:24][CH2:25][C:26]1[CH:38]=[CH:37][C:29]2[C:30]([O:33][CH2:34][O:35][CH3:36])=[N:31][O:32][C:28]=2[CH:27]=1)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]
Reactant: COCOc1noc2cc(COc3ccc(C(=O)c4ccc(OC5CCCC5)cc4O)cc3CCC(=O)O)ccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1noc2cc(COc3ccc(C(=O)c4ccc(OC5CCCC5)cc4O)cc3CCC(=O)OCOC(=O)C(C)(C)C)ccc12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.04 g of 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and 512 mg of potassium carbonate were suspended in 10 mL of N,N-dimethylformamide, to which 0.29 mL of chloromethyl pivalate was added, and this mixture was stirred for 2 hours at 40° C. Then, water and ethyl acetate were added to the reaction mixture, and the organic phase was separated therefrom. The remaining aqueous phase was extracted with ethyl acetate, and organic phases were combined together. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 1.02 g of {[3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl pivalate as light yellow oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.IC>O1CCCC1.CCCCCC>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[CH3:1]
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Cl)cncc1Cl
Temperature: -10 °C
Yield: 68 %

Procedure:
Diisopropylamine (70 mL, 500 mmol) is dissolved in dry tetrahydrofuran (500 mL), the solution is cooled to −10° C. and buthyl lithium (2.5 N in hexane, 210 mL, 525 mmol) is added dropwise under stirring. After 30 minutes the solution is cooled to −20° C. and 3,5-dichloropyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) is added dropwise. The solution is stirred at −10° C. for 30 minutes, then cooled to −70° C. and iodomethane (50 mL, 1.6 mol) in tetrahydrofuran (100 mL) is added dropwise. The reaction mixture is allowed to warm to room temperature, quenched with water (100 mL) and extracted with diethyl ether (3×100 mL); the combined organic layers are dried over sodium sulphate (5 g) and evaporated to dryness. The crude product is crystallized twice from aqueous ethanol, then from hexane to afford 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([NH2:33])[CH2:29][CH2:28]1)[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][N:30]3[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: CCN1CCN(N)CC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(NC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (20 mL) was treated with 4-ethylpiperazin-1-amine (0.12 g). T3P (50% in EtOAc, 0.84 mL) and DIPEA (0.24 mL) were added simultaneously and the reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-cold water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.280 g of crude compound. Purification by combi-flash chromatography (eluting with 2% MeOH in CH2Cl2) followed by purification on a preparative TLC plate (eluting with 10% MeOH in CH2Cl2) afforded 60 mg (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(4-ethylpiperazin-1-yl)acrylamide. 1H NMR (400 MHz, CF3COOD) δ: 10.75 (s, 1H), 8.31-8.29 (d, J=10.2H), 7.98 (s, 1H), 7.21-7.23 (d, 1H), 6.08-6.10 (d, 1H), 3.52-3.54 (m, 3H), 3.36 (s, 1H), 3.11 (m, 8H), 1.19-1.22 (m, 3H); LCMS for C19H21F6N6O [M+H]+ 463.40; found 463.23 (RT 2.43 min, purity: 98.63%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2CC=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[C:16](=[O:18])[CH3:17])(=O)C.C([O-])(=[O:21])C.II>C([O-])(=O)C.[Ag+].O.C(O)(=O)C.N1C=CC=CC=1>[C:16]1([OH:18])[C:17]2[CH2:10][C@H:1]([OH:11])[C@H:2]([OH:21])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Oc1cccc2c1CC=CC2
Reactant: CC(=O)OC(C)=O
Agent: [Ag+]
Agent: II
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc2c1C[C@H](O)[C@H](O)C2
Reaction time: 16 h

Procedure:
A solution of 29.2 g. (0.2 mole) of 5,8-dihydro-1-naphthol and 40 ml. of acetic anhydride in 100 ml. of pyridine is prepared. After 16 hr. the solvent is removed in vacuo and the residue dissolved in ether and washed with 200 ml. of 5% hydrochloric acid, water, 200 ml. of 10% sodium hydroxide, saturated salt solution and dried. Solvent removal gives 34.2 g. (90.5%) of crude acetate which is dissolved in 900 ml. of acetic acid and 36 ml. of water. 53.3 g. (0.32 mole) of silver acetate is added followed by 40.6 g. (0.16 g-atom) of iodine. The slurry is heated with good stirring at 85° ± 10° for 3 hr. under nitrogen, cooled and filtered. The filtrate is evaporated in vacuo and the residue dissolved in 250 ml. of methanol and cooled to 0°. A solution of 40 g. of sodium hydroxide in 200 ml. of water is added under nitrogen and the mixture stirred overnight. The bulk of the methanol is removed in vacuo whereupon a solid forms. The solid is separated by filtration, dissolved in 150 ml. of water and acidified with 20 ml. of concentrated hydrochloric acid. Cooling gives a solid which is filtered and dried to give 16.5 g. 2,3-cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol) m.p. 184.5°-187°. Three recrystallizations from absolute ethanol give the analytical sample, m.p. 188°-188.5°.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[CH:17][S:16][C:15]=1C(O)=O)([O-:7])=[O:6].C1[CH2:26][O:25]CC1.[N-:27]=[N+]=[N-].[Na+]>C1C=CC=CC=1.O>[N+:5]([C:8]1[C:9]2[C:14]3[CH:18]=[CH:17][S:16][C:15]=3[NH:27][C:26](=[O:25])[C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: O=C(O)c1sccc1-c1ccccc1[N+](=O)[O-]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=c1[nH]c2sccc2c2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 2.2 %

Procedure:
2 ml of thionyl chloride were added to a solution of 3-(2-nitrophenyl)thiophen-2-carboxylic acid (9) (3.5 g, 14 mmol) in 20 ml of anhydrous benzene and the mixture was refluxed for 2 hrs. The solvent and the excess thionyl chloride were removed under vacuum and the residue was taken up using 50 ml of THF, and NaN3 (1.37 g, 21 mmol) in 10 ml of water was added rapidly to this stirred solution at 0° C. The mixture was left for 1 hr at room temperature with stirring, poured into 100 ml of ice and water and extracted with ethyl ether (4×50 ml), the separated organic layer was dried over anhydrous sodium sulphate and leaving it for 2 hrs with stirring. It was evaporated under vacuum and coevaporated with anhydrous benzene (3×50 ml). It is evaporated and the residue was solubilized in 60 ml of o-dichlorobenzene and refluxed using a Dean-Stark apparatus. The mixture was left under reflux for 20 hrs with stirring, then cooled and evaporated. The mixture was subjected to flash chromatography, and elution with chloroform yielded the compound 9-nitrothieno-[2,3-c]-isoquinolin-5(4H)-one (0.075 g, 2.2% yield) as a yellow solid (M. Pt, 255–258° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[CH2:29][CH2:28][CH2:27]1.[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][N:44]=2)[CH:39]=[CH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[NH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:31][CH2:32][CH2:33]1.[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:44]3[C:45]4[C:40](=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:41][CH2:42][CH2:43]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: c1cnc2ncccc2c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCCc2cccnc21

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (208 mg, 0.50 mmol), 1,2,3,4-tetrahydro-[1,8]naphthyridine [(135 mg, 1.0 mmol) 1,2,3,4-tetrahydro-[1,8]naphthyridine was prepared freshly from 1,8-napthyridine via hydrogenation over Pt2O], BOP (486 mg, 1.1 mmol), DIEA (185 mg, 1.4 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 4-chloro-N[5-chloro-2-(3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z: 531.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH:28]1[C:29]2[C:24](=[CH:23][C:22]([CH2:21][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: ClCc1ccc2cnccc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccc4cnccc4c3)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by MDE 32048 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 56 mg of 4-(isoquinolin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 21 as a brown solid (67 mg, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)=[O:19]>>[ClH:1].[OH:29][C:24]1[NH:25][C:26]2[C:22]([C:23]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:6][N:7]=1)=[CH:21][C:20]([C:18]([NH:17][CH3:16])=[O:19])=[CH:28][CH:27]=2
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Product: CNC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Product: Cl
Yield: 12 %

Procedure:
The title compound was prepared as described for Example 101 using 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]morpholine and N-methyl-2-oxoindoline-5-carboxamide. Yield: 12%: 1H NMR (D2O, 400 MHz) δ 7.82 (d, J=2 Hz, 1H), 7.58 (dd, J=9, 2 Hz, 1H), 7.45 (br s, 1H), 7.28 (m, 2H), 6.92 (d, J=8 Hz, 1H), 4.16 (s, 2H), 4.12 (m, 2H), 3.79 (m, 2H), 3.46 (m, 2H), 3.24 (m, 2H), 2.90 (s, 3H); MS (TSP) m/z 367 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[P:11]([Cl:16])(Cl)(Cl)(Cl)[Cl:12].C(O)=[O:18].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][P:11]([Cl:16])([Cl:12])=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccc(Cl)cc1

Procedure:
A suspension of 68 g, (0.44 mole) of 4-chlorobenzamide, 91 g (0.44 mole) of phosphorus pentachloride and 700 ml of AR carbon tetrachloride was heated at 65°-70° for 25 min. The solution was cooled to 20° and 20.7 g (0.44 mole) of 97% formic acid added dropwise. After the HCl gas evolution had nearly stopped, ca. 30 min., the precipitate was collected by filtration, washed with AR carbon tetrachloride and air-dried to give 103 g, m.p. 114.5°-115.5°.
Reaction SMILES: Cl.[F:2][C:3]([F:41])([F:40])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22].[C:42](OC(=O)C)(=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:41][C:3]([F:2])([F:40])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:42](=[O:44])[CH3:43])[CH2:17][CH2:18]2)[CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(1-aminocyclohex-4-yl oxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.090 g, 0.15 mmol) from Example 41 in CH2Cl2 (4 mL) was added acetic anhydride (0.031 mL, 0.3 mmol) and DIEA (0.052 mL, 0.3 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (20 mL), H2O (10 mL), and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH2:26])=[N:3]1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH:26][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])=[N:3]1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Product: Cn1nc(CNC(=O)Nc2ccccc2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (0.75 g) and phenyl isocyanate (0.25 ml) in dry acetonitrile was stirred at 30° for 3 h. The solvent was removed in vacuo and the solid residue was crystallized from methyl acetate and petroleum ether (b.p. 60°-80°) to give the title compound (0.94 g) as a white solid, m.p. 120°-1°. T.l.c. System A, Rf 0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.[H-].[Na+].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:12])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of the title compound of Example 3 Step D (240 mg, 0.63 mmol) in DMF (2.5 mL) was added NaH (30 mg, 60% suspension in mineral oil, 0.75 mmol). After 15 min, 4-tert-butylbenzyl bromide (0.126 mL, 0.69 mmol) was added, and the resultant mixture was stirred for 1.5 h, whereupon it was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25%, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS B, tr=3.30 min, m/z 530.3 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.5 Hz, 2H), 7.63 (d, J=2.0 Hz, 1H), 7.29-7.23 (m, 4H), 7.15 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 5.78 (ABq, J=16.0 Hz, Δν=71.0 Hz, 2H), 3.87 (s, 3H), 3.62 (dddd, J=8.5, 8.5, 5.5, 5.5 Hz, 1H), 3.08 (dd, J=14.0, 8.5 Hz, 1H), 2.78 (dd, J=14.0, 5.5 Hz, 1H), 1.76-1.70 (m, 1H), 1.52-1.45 (m, 1H), 1.26 (s, 9H), 1.23-1.18 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:3]1.[C:21]([O-])([O-])=O.[K+].[K+].CC(C)=O.IC>C(OCC)(=O)C>[CH3:21][N:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[B:4]1[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a round bottom flask under nitrogen were added N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (250 mg, 0.84 mmol), K2CO3 (140 mg, 1.01 mmol) and acetone (5.0 mL). Iodomethane (0.06 mL, 1 mmol) was then added to the mixture dropwise and the reaction stirred for 18 hours at rt. The reaction was then diluted with ethyl acetate (100 mL), washed with water (2×) and brine (1×), dried (Na2SO4) and concentrated to dryness. The crude product was purified by FCC providing the title compound (230 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=7.3, 1.8, 1H), 7.51-7.43 (m, 1H), 7.40-7.29 (m, 2H), 3.32 (s, 3H), 2.93 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:20]I>>[CH3:6][O:5][C:3](=[O:4])/[C:2](/[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:1](/[CH3:20])\[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CI
Reactant: Cl[Mg]Cc1ccccc1
Product: COC(=O)/C(C)=C(/Cc1ccccc1)C(=O)OC
Yield: 24 %

Procedure:
Dimethyl acetylenedicarboxylate was reacted with benzylmagnesium chloride and methyl iodide in the same manner as Example 1 to give the title compound as oil (yield: 24%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14](=[S:16])[NH2:15])=[CH:5][N:4]=1.CO[CH:19](OC)[CH2:20]Br>C(O)C.Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)=[CH:5][N:4]=1
Reactant: COC(CBr)OC
Reactant: CSc1ncc(C(N)=S)c(-c2cccs2)n1
Agent: Cl
Solvent: CCO
Product: CSc1ncc(-c2nccs2)c(-c2cccs2)n1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
2-(Methylthio)-4-(thiophen-2-yl)pyrimidine-5-carbothioamide (0.3 g, 1.12 mmol) suspended in ethanol (2 mL) was treated with bromoacetaldehyde dimethylacetal (0.158 mL, 1.34 mmol). The reaction was stirred at reflux overnight. No product formation was observed by thin layer chromatography in 20% ethyl acetate/hexanes. Another equivalent of bromoacetaldehyde dimethylacetal was added to the reaction in addition to a few drops of concentrated hydrochloric acid and the reaction kept at reflux for another 3 h. The reaction was cooled down to room temperature and the volatiles removed in vacuo. A solution of saturated sodium bicarbonate was added to the residue, which was extracted with dichloromethane. The organic layer was dried with sodium sulfate and purified by flash chromatography using a gradient of 20 to 60% of ethyl acetate in hexanes. The product was obtained as a brown solid (0.18 g). MS (M+H)+ 292.