Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Br[C:24]1[S:25][C:26]2[C:32]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:31]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:30]([CH3:48])=[CH:29][C:27]=2[N:28]=1.C(Cl)[Cl:50]>>[Cl:50][C:24]1[S:25][C:26]2[C:32]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:31]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:30]([CH3:48])=[CH:29][C:27]=2[N:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCOC(=O)C(=O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above residue was dissolved in CH2Cl2 (33 mL), cooled to 0° C. and Dess-Martin periodinane (2.54 g, 5.99 mmol) was added portion-wise. After stirring for 2 h, more Dess-Martin periodinane (0.25 g, 5.99 mmol) was added. After 1 h, reaction was quenched with Na2S2O3 solution and stirred for 30 minutes. The mixture was diluted with CH2Cl2, washed with water, saturated sodium bicarbonate solution, brine and dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 20% EtOAc/Hex) to give product contaminated with ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-oxoacetate 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[N:23][CH:22]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[N:23][CH:22]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2cnc(-c3cccc(C(F)(F)F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 5-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370C): MS (ES) m/z 476 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([CH2:31][OH:32])[CH:28]([OH:33])[CH:27]3[OH:34])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.N1C=CN=C1.[C:49]([Si:53](Cl)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([CH3:52])([CH3:51])[CH3:50].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]([OH:34])[CH:28]([OH:33])[CH:29]([CH2:31][O:32][Si:53]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO)C(O)C3O)c2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(O)C3O)c2n1

Procedure:
A solution of the product of step (a) (1.11 g), imidazole (417 mg) and tert-butylchorodiphenylsilane (0.75 ml) in dry DMF (4 ml) was stirred for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were dried, concentrated and purified (SiO2, petrol:acetone 3:1 as eluant) to give the subtitle compound (1.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:24][C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)[CH2:10][CH2:9]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCN(c3ccccc3Cl)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
A solution of 8.0 g (0.031 mol) of 1-(2-chloro-phenyl)-piperazine in 300 ml of tetrahydrofuran was treated with 22 ml (0.16 mol) of triethylamine and 11.5 g (0.031 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 5.5 g (55%) of 5-[4-(2-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as beige crystals; m.p. 2:30°-235°.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([OH:38])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH:22](=[O:38])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCC/C=C/CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/C=O
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a stirred suspension of 60.6 g (0.161 mol) pyridinium dichromate in 100 mL of dichloromethane was added 25.7 g (0.107 mol) of trans-2-hexadecenol. After 4 h at 25° C., the mixture was filtered (through Celite diatomaceous earth) and the resulting brown solution refiltered through Florisil, an activated magnesium silicate in the form of hard, porous, stable, white granules that are free from dusting sold by Floridin Co. The colorless solution obtained was concentrated in vacuo to 21.8 g (86%) of a white solid. Distillation (90°-100° C./0.40-0.45 torr) provided 19.1 g (75%) of pure trans-2-hexadecenal as a white waxy solid. IR (thin film as melt) 2920, 2850, 1695, 1465, 975 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ9.53 (d, 1, J=6.7 Hz, CHO), 6.88 (overlapping dt, 1, J=15.7, 6.7 Hz, OHCCH=), 1.53 (m, 2, CH 2 CH3), 1.1-1.2 (m, 20, CH2CH2CH2), 0.90 (t, 3, J=7 Hz, CH2CH3). Rf (15% ethyl acetate:hexanes):trans-2-hexadecenol, 0.19 trans-2-hexadecenal, 0.44. MS(FD) m/e 238 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:28][N:27]([CH2:24][CH2:25][CH3:26])[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2=O)cc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1NC(c2ccc(C)cc2)C2=C1C(=Cc1ccc(C)cc1)CSC2
Yield: 73 %

Procedure:
A mixture of tetrahydro-3,5-bis-(4-methylphenylmethylene)-4H-thiopyran-4-one (6.7 g, 20 mmole) and n-propylhydrazine (1.6 g, 22 mmole) in methanol (250 ml) is heated at reflux temperature for 5 hours, then cooled overnight. The pale yellow precipitate is collected by filtration. The filtrate is concentrated to about 50 ml and additional precipitate is again collected by filtration and combined with the previous batch to give 5.5 g of a crude product mixture.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][OH:13].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].P([O-])([O-])([O-])=O>C1COCC1>[CH3:16][S:17]([O:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC=COC1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCC=COC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
The alcohol 106 (147 mg, 0.791 mmol) was added to a suspension of NaH (60% in oil, 38 mg, 0.95 mmol, 1.2 equiv) in THF (5 mL). The resulting mixture was stirred at 25° C. for 30 min and cooled to 0° C. before CH3SO2Cl was added dropwise. The reaction mixture was stirred 15 min at 0° C. and 15 min at 25° C. Phosphate buffer (100 mL, pH 7) was added and the mixture extracted with CH2Cl2 (2×50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 2×25 cm, 30% EtOAc-hexane containing 2% Et3N) afforded 107 (205 mg, 208 mg theoretical, 98%) as a colorless oil as a mixture of E- and Z-olefin isomers (50:50): 1H NMR (CDCl3, 400 MHz) δ 6.24 (dt, J=12.3, 1.3 Hz, 0.5 H), 6.14 (dt, J=6.3, 1.4 Hz, 0.5H), 5.05 (dt, J=12.3, 7.5 Hz, 0.5H), 4.88 and 4.85 (two t, J=3.1, 3.4 Hz, 1H), 4.43 (m, 0.5H), 4.15 (m, 1H), 3.83 and 3.54 (two m, 2H), 3.05 (s, 3H), 2.17 and 1.98 (two m, 2H), 1.85-1.49 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II)chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0→10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[N:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.O>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:19][CH:20]=1
Reactant: Cn1nnc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A solution of (3-methyl-5-phenyl-3H-[1,2,3]triazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 48 mg, 1.1 mmol) in THF (1.5 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (189 mg, 1.1 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (203 mg, 63%) as an off white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26]
Reactant: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.86 g, 5 mmol) (prepared as described in Example 73) was combined with tert-butyldimethylsilyl chloride (1.05 g, 7 mmol) and imidazole (0.75 g, 11 mmol) in dimethylformamide (35 mL). The reaction mixture was heated at 50° C. for 24 hours, cooled to room temperature and added to water, stirred for 30 minutes, filtered and dried to give 1.88 g of 3-(2-chlorophenyl)-7-(trans-4-tert-butyl-dimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, m.p.289-294° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:35]=[CH:34][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:33])[C:15]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37].N1C=CC=CC=1>CC(C)=O>[CH3:32][C:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:34]=[CH:35][C:3]([NH:2][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 74.7 %

Procedure:
A solution of Example 37B (0.374 g, 0.722 mmol), mesyl chloride (0.224 mL, 2.89 mmol), and pyridine (0.467 mL, 5.78 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.302 g, 75%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-amino-3,4-dihydro-2H-naphthalen-1-one (20.5 g, 127 mmol) in 25% HBr (aq) (1017 ml) at 0° C. was added a solution of sodium nitrite (10.53 g, 153 mmol) in water (50 ml) dropwise at a rate as to maintain the temperature below 3°. The cooled reaction mixture was then added to a cooled solution of copper(I) bromide (18.79 g, 131 mmol) in HBr (98 ml, 865 mmol). When the addition was done, the reaction mixture was stirred at 0° C. for 1 h, then warmed to rt. Water (380 mL) was added and the product was extracted with a mixture of Et2O/EtOAc (8:2, 3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark brown crude oil. The crude was purified by distillation (3 mm Hg) to give 16.415 g of 6-bromo-3,4-dihydro-2H-naphthalen-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[N:19]1([C:28](Cl)=O)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1>C1(C)C=CC=CC=1>[N:19]1([C:28]2[O:9][C:8](=[O:10])[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:11]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)n1nnc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc2nc(-n3nnc4ccccc43)oc(=O)c12
Reaction time: 12 h
Yield: 22.6 %

Procedure:
A solution of 960 mg of 6-methyl anthranilic acid in 30 ml of dry toluene containing 1.77 ml of dry triethylamine, which had been stirred for 30 minutes, was added to a solution of 2.1 gm of 1-benzotriazole carboxylic acid chloride in 30 ml toluene over a period of 30 minutes, and stirred for 12 hours. The resulting precipitate was filtered. The filtrate was reduced to one-half of its initial volume, and the resulting solids isolated by filtration. The combined residues were washed with water, dried under high vacuum and recrystallized from chloroform, giving 400 mg of 2-(1-benzotriazolyl)-5-methyl-4H-3,1-benzoxazin-4-one, m.p. 214°-215° C. (decomp.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][C:13]1[C:12]2[C:16](=[CH:17][C:9]([Cl:8])=[CH:10][CH:11]=2)[NH:15][N:14]=1)=[O:6]
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Product: O=C(CCCCl)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 6 °C
Reaction time: 19 h

Procedure:
0.67 cm3 of 4-chlorobutyryl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, after cooling to about 6° C. in an ice bath, and the mixture is then allowed to return to room temperature over 19 hours. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 45° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The precipitate is filtered off and rinsed with 15 cm3 of ethyl acetate and 5 cm3 of dichloromethane. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 45° C.); after drying (90 Pa; 50° C.), 343 mg of 4-chloro-N-(6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a pale yellow solid melting at 220° C.
Reaction SMILES: C1(O)C=CC=CC=1.[OH-].[Na+].[CH3:10][NH:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1.[O:21]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=O)C1C=CC=CC=1>C1COCC1>[CH3:10][N:11]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:21])[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 15 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of phenol (2.18 g, 23.2 mmol) in THF (25 mL) was added 50% NaOH solution (1.86 g, 23.2 mmol) at ambient temperature. After the exotherm subsided, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.95 g, 23.2 mmol) was added. The solution was cooled to 15° C., and then a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 25 mL of THF was added slowly. An ice bath was used to maintain the temperature between 15 and 20° C. Following a 5 mL THF rinse, the reaction was allowed to warm to ambient temperature. After three hours, an additional aliquot of 50% NaOH solution (90 mg, 2.3 mmol) was added. After 19 hours, the reaction was quenched by the addition of 100 mL of water and the THF removed under reduced pressure. The remaining aqueous phase was washed with MTBE (3×60 mL), toluene (70 mL) was added, and the pH was adjusted to 3.7 with 4 N HCl. The layers were separated, and the aqueous phase was extracted with two additional aliquots (70 mL) of toluene. The combined toluene extracts were concentrated in vacuo. The resulting oil was crystallized using toluene and heptane to give the title compound (5.1 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][OH:25])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[Si:35]([O:25][CH2:24][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C:10]1=[O:23])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution (20 mL) of tert-butyl 7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-6-oxo-1,4-oxazepane-4-carboxylate (1.27 g) in DMF were added imidazole (266 mg) and tert-butyldimethylchlorosilane (540 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, the mixture was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: [C:1]([CH:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[C:26](Cl)([Cl:28])=[O:27]>O1CCCC1>[Cl:28][C:26]([O:25][CH:18]([C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:27]
Reactant: O=C(Cl)Cl
Reactant: NCCCCCC(O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: NCCCCCC(OC(=O)Cl)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of FMOC-6-aminohexanol (617.2 mg, 1.5 mmol) in tetrahydrofuran (6 ml) was heated and then cooled to room temperature. To this solution was then added phosgene (2.9 ml, 1.93M in toluene). The reaction was stirred at room temperature for 15 hours and concentrated in vacuo to yield FMOC-6-aminohexanol chloroformate which was used immediately without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)cs1
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
According to the procedure of Example 32, 2.48 g (12.0 mmoles) of 4-bromo-2-thiophenecarboxylic acid (prepared according to Lawesson, S. O., Arkiv. for Kemi. 11:317 (1957)) and 10 ml of thionyl chloride were combined and heated. The reaction gave 2.99 g of 4-bromo-2-thiophenecarbonyl chloride as a dark oil. Following the procedure of Example 32, the acid chloride, 2.11 g (10.0 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.67 g (30.0 mmoles) of 4-(N,N-dimethylamino)pyridine were reacted in N,N-dimethylformamide to give 4.03 g of a crude orange solid. Recrystallization gave 2.67 g (6.68 mmoles, 66.8% yield) of title compound as a yellow crystalline solid, m.p. 217°-219° C. (dec.) (2-butanone).