Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([C:27](SC)=[N:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][NH2:39]>CN(C=O)C>[CH3:38][NH:39]/[C:27](=[N:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[N:22]1[CH2:23][CH2:24][C:25]2[N:26]=[C:18]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[S:19][C:20]=2[CH2:21]1
Reactant: CN
Reactant: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)sc2C1
Agent: Cl
Solvent: CN(C)C=O
Product: CN/C(=N\c1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)sc2C1

Procedure:
A solution of methyl 2-({2-[(tert-butoxycarbonyl)amino]phenyl}carbamoyl)-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate obtained form step I (1 eq), and methylamine HCl (60 eq) in DMF was heated at 50° C. in a sealed tube for 72 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford the tert-butyl {2-[({5-[(E)-(methylamino)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbonyl)amino]phenyl}carbamate
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH2:18]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH:33]=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCO.N1CCCCC1>[C:15]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])(=[O:16])[NH2:17]
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=CC1CCCN1C(=O)OCc1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and benzyl-2-formylpyrrolidine-1-carboxylate (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15]2>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([NH:2][OH:3])=[NH:23])[CH:16]=[CH:15]2
Reactant: N#Cc1ccc2cc(Br)ccc2c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
2.48 g hydroxylamine-hydrochloride and 5.68 ml triethylamine are added to 4.10 g of 6-bromo-2-cyano-naphthalene in 100 ml of ethanol and the reaction mixture is refluxed for four hours. After cooling to ambient temperature the solvent is distilled off in vacuo using the rotary evaporator and the flask residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Br:18][C:19]1[C:20]([CH3:29])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24]>>[Br:18][C:19]1[C:20]([CH3:29])=[N:21][N:22]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[C:23]=1[CH3:24]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1nn(CC(=O)O)c(C)c1Br
Product: Cc1nn(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c(C)c1Br
Yield: 32.4 %

Procedure:
Example 35 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (0.047 g) to give the title compound (0.032 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1.[C:24](O)(=[O:26])C>O.[C].[Pd]>[CH3:11][C:9]1([CH3:12])[O:10][C:5]2=[CH:4][C:3]3[NH:21][C:24](=[O:26])[NH:1][C:2]=3[CH:20]=[C:6]2[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=2[O-:19])[CH2:8]1
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c([N+](=O)[O-])cc2O1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc3[nH]c(=O)[nH]c3cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 632 mg 2-(6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine 1 -oxide in 10 ml acetic acid, was added 50 mg of 10% palladium carbon, and catalytic hydrogenation was performed. The reaction mixture was filtered by the use of Celite, the solvent was distilled off from the filtrate under reduced pressure, the residue was dissolved in 10 ml tetrahydrofuran, 5 ml tetrahydrofuran solution containing 324 mg carbonyldiimidazole was added under ice cooling, and the mixture was stirred overnight at room temperature. The precipitate which separated out was filtered off, the solvent was distilled off from the filtrate under reduced pressure, the residue thus obtained was dissolved in water, the aqueous solution was washed with chloroform and allowed to stand at room temperature for one hour, and the crystals which separated out were collected by filtration, thus giving 130 mg of 2-(7,8-dihydro-6,6-dimethyl-2-oxo-6H-[1,4]oxazino[2,3-f]benzimidazolin-8-yl)pyridine 1-oxide.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[N:29]1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)[CH:38]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1cccc(-n2cccn2)c1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3cccc(-n4cccn4)c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 3-(1H-pyrazol-1-yl)phenylboronic acid, the title compound was synthesized following the procedures described Example 108.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:9][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:11]
Reactant: CCc1cc(O)cc(CC)c1-c1cccc(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
To a solution of 2′,6′-diethyl-4′-hydroxybiphenyl-3-carbaldehyde (2.44 g, 9.59 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.73 g, 12.5 mmol), and the mixture was stirred at 90° C. for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:29]=2[N:30]=1.CCN(C(C)C)C(C)C>CC#N>[F:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[N:13]=[C:14]([CH3:24])[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Fc1ccc2oc(Cl)nc2c1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(F)ccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (40 mg, 115 μmol), 2-chloro-5-fluorobenzoxazole (24 mg, 138 μmol) and DIPEA (60 μl, 345 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3 and brine. The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 483 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])(=[O:5])=[O:4].C1COCC1.[OH-].[Li+]>O>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])(=[O:5])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)N(C)CCN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCN1CCOCC1)S(=O)(=O)c1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 3-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)-thiophene-2-carboxylate (Int. 47) (510 mg, 1.464 mmol) in a 1:1 mixture of THF and H2O, lithium hydroxide (351 mg, 14.64 mmol) was added, and the mixture was stirred at RT overnight. The organic solvent was evaporated and the aqueous residue was acidified with 2N HCl (pH=7); the precipitate was collected by filtration affording 3-(N-methyl-N-(2-morpholinoethyl)-sulfamoyl)thiophene-2-carboxylic acid (Int. 48) (410 mg, 1.226 mmol, MS/ESI+334.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][N:11]=[C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=12.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:17]1[C:12]2[C:13](=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[O:10][N:11]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3Cl)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cccc23)c(Cl)c1
Yield: 71.8 %

Procedure:
A mixture of 10.9 g (0.039 mole) of 3-(2,4-dichlorophenyl)-7-methyl-2,1-benzisoxazole, 7.1 g (0.040 mole) of N-bromosuccinimide, 0.1 g of dibenzoylperoxide and 200 ml of carbon tetrachloride was heated at reflux under illumination of a flood lamp for 2 hr. The mixture was filtered and the filtrate was washed once with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give a solid as residue. The solid was recrystallized from 2-propanol to yield 10.0 g (71%) of tan solid, m.p. 108°-110° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1[CH:28]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1/[CH:28]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.8 %

Procedure:
A solution 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide (Ex-55A, 830 mg, 2.44 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44 mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Column chromatography (5% MeOH in dichloromethane) gave 772 mg (57%) of the title compound as a brown solid, mp 64–68° C. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76 (quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s, 4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for C29H40N4O5S: 557.2798 [(M+H)+]; Found: 557.2798.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[C@H:10]([N:18](C(OC(C)(C)C)=O)[CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[C@H:10]([NH:18][CH3:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A solution of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenyl-propionylamino)propyl acetate (862 mg, 2.28 mmol) in dichloromethane (3 mL) was cooled to 0° C. Trifluoroacetic acid (3 mL) was added. The solution was stirred for 10 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (50 mL) and the solvent was removed in vacuo. The procedure was repeated twice. The crude product was purified by flash chromatography on silica (70 g) with dichloromethane/methanol/25% ammonia in water (100:10:1) to give 602 mg of 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:15][CH:16]=1)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with benzylamine there was obtained tert-butyl (3RS,4RS)-4-(4-benzylcarbamoyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; MS: 551 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethoxy)phenyl)boronic acid gave 157. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.40 (dd, J=7.9, 2.3 Hz, 1H), 7.84 (s, 1H), 7.54-7.44 (m, 5H), 4.89-4.80 (m, 1H), 4.69-4.53 (m, 1H), 4.41-4.28 (m, 1H), 4.21-4.02 (m, 1H), 3.77 (s, 3H), 3.48-3.38 (m, 1H), 2.13-2.02 (m, 1H), 1.91-1.72 (m, 3H). LCMS (ES+) m/z 515 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(N)nc4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-(6-Aminopyridin-3-yl)-1,3-dihydroindol-2-one (56 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3](O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C=Cc1ccccc1[N+](=O)[O-]

Procedure:
To 40 g (179 mmol) of 3,3-dimethyl-1-(2-nitrophenyl)butan-2-ol in 400 ml of toluene at room temperature are added 23.44 g (197 mmol) of thionyl chloride, and the mixture is boiled under reflux for 2 h. After washing with 100 ml of saturated sodium bicarbonate solution and distilling the organic phase at 116° C./12 mbar, 20 g (48% of theory) of 1-[(1E)-3,3-dimethylbut-1-en-1-yl]-2-nitrobenzene are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>>[NH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:17]2[N:18]=[C:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:36])[C:14]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])[C:15]=3[N:16]=2)[CH2:38][CH2:39]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from compound N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and 4-piperidinamine by following the General Procedure for Sulfoxide/Sulfone/Sulfone Displacement, as disclosed above. The concentrated reaction mixture is precipitated with ethyl acetate/hexanes, and filtered. The desired product is obtained as a yellow solid (75 mg, 100%) 94% pure by HPLC: LC-MS m/z 531 (M+H)+, 1.65 min (ret time).
Reaction SMILES: C[O:2][CH:3]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=3[O:30][CH3:31])=[CH:12][CH:13]=2)[N:8]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:7]=1)OC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:31][O:30][C:16]1[CH:17]=[C:18]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH:3]=[O:2])=[N:7][N:8]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[CH:13][CH:12]=1
Reactant: COc1cc(OCOCC[Si](C)(C)C)ccc1-c1ccc2c(C(OC)OC)nn(COCC[Si](C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCOCC[Si](C)(C)C)ccc1-c1ccc2c(C=O)nn(COCC[Si](C)(C)C)c2c1
Yield: 99.5 %

Procedure:
3-(1,1-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (1.1 g, 1.92 mmol) was stirred in 1% TFA/CH2Cl2 (20 mL) for 1 h at rt. Concentration in vacuo yielded 1.01 g (100%) of 6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde as a clear oil. 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 8.28 (d, 1H, J=8.4 Hz), 7.73 (s, 1H), 7.55 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H, J=8.4 Hz), 6.72–6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.78–3.84 (m, 5H), 3.61 (t, 2H, J=8.1 Hz), 0.89–1.03 (m, 4H), 0.03 (s, 9H), −0.05 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(I)c1
Reactant: CC(=O)Nc1ccccc1
Product: COc1cccc(N(C(C)=O)c2ccccc2)c1
Yield: 67 %

Procedure:
Using acetanilide (3.7 g) and 3-iodoanisole, a reaction was made in the same manner as is 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:3 to 1:2) produced 3-methoxy-N-phenylacetanilide (4.44 g; yield, 67%) as a pale brown oil.
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]#[C:23][Si](C)(C)C)=[CH:21][C:16]=2[C:15]2[C:14](=[O:28])[NH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[K+]>CO.O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:8]([NH:7][CH:2]([CH3:1])[C:3]([CH3:4])([CH3:6])[CH3:5])=[N:9][C:10]3[CH:11]=[CH:12][NH:13][C:14](=[O:28])[C:15]=3[C:16]=2[CH:21]=1)#[CH:23]
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(C#C[Si](C)(C)C)ccc12)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-[(1,2,2-trimethylpropyl)amino]-9-[(trimethylsilyl)ethynyl]benzo[c]-1,6-naphthyridin-1(2H)-one (20 mg, 0.05 mmol) in MeOH (3.0 mL) was added KOH (6.0 mg, 0.09 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, concentrated to afford 9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.62 (d, J=10.1 Hz, 1H), 7.31 (s, 1H), 6.62 (s, 1H), 3.23 (s, 1H), 1.25 (m, 3H), 1.04 (s, 9H). LRMS calculated for C20H21N3O [M+H]+, 320; found 320.