Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-[2-hydroxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylate (syn-isomer) (1.45 g.) in trifluoroacetic acid (25 ml.) was allowed to stand at room temperature for 10 minutes. The trifluoroacetic acid ws evaporated under reduced pressure, the residue dissolved in ether (50 ml.) and extracted with saturated aqueous sodium bicarnbonate. The combined aqueous extracts were acidified (2N hydrochloric acid) and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated. The residue was redissolved in ethyl acetate (5 ml.) and added dropwise with stirring to petroleum (b.p. 40°-60° C; 500 ml.). The precipitated solid was filtered and dried, giving 3-acetoxymethyl-7β-[2-hydroxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylic acid (syn-isomer) (0.515g; 42%), [α]D + 56° (c 0.5, DMSO), λmax. (EtOH) 253 nm (ε 16,600), νmax. (Nujol) 33SO (NH and OH), 1778 (β-lactam), 1720 (CO2H and acetate), 1666 and 1540 cm.-1 (CONH) τ (DMSO-d6) values include 0.32 (doublet, J 9 Hz; NH) 2.15-2.7 (multiplet; aromatic protons), 7.8 (singlet; CH3CO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:30]=[O:31])[C:24]=1[F:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH2:13]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:30]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:31])[C:24]=1[F:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: Clc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.524 g, 3.43 mmol) in 5.00 mL of methanol. Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (4, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ethyl acetate to give the desired compound (6, 710 mg, 46%). MS (ESI) [M+H+]+=444.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:21]=[CH:20][C:16]([CH:17]=[N:18][OH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].O>CN(C=O)C>[Cl:1][C:16]1([CH:17]=[N:18][OH:19])[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:21][CH2:20]1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C1=CCC(Cl)(C=NO)C=C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (8.1 g, 61 mmol) was added to a solution of 4-tert-butylbenzaldehyde oxime (9 g, 50.1 mmol) in DMF (50 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being cooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-4-tert-butylbenzene was obtained as a yellowish solid (10.7 g).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:36][CH2:35]1
Reactant: OCCN1CCN(c2ncccn2)CC1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=C(OCCN1CCN(c2ncccn2)CC1)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (1.0 g, 6.0×10-3 mol) in 25 ml of chloroform under a dry nitrogen atmosphere, was added carbonyldiimidazole (0.98 g, 6.0×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 2-[1-(2-pyrimidyl)-4-piperazinyl]ethanol (1.25 g, 6.0×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, Rf=0.45) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (1.76 g, 61% yield), mp.=219°-220° C.
Reaction SMILES: F[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-:18].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:18][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [OH-]
Reactant: CCCCCCOc1cccc(C(N)=O)c1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCCCOc1cccc(C(N)=O)c1O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
A mixture of 2-fluoro-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol) copper (0.015 g, 0.2 mmol) and NaOH (2.5 ml) was stirred at 100° C. for 14 hrs. After completion of reaction the reaction mixture was acidified and extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-4000 using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H). MS ES+ (229.0 M+2H adduct). HPLC (Method 7) Rt=11.16 min.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[N:18]=[N:17]1.[OH-].[Na+].O>C(O)C>[I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[N:17]1
Reactant: CCOC(=O)c1cn(-c2ccc(C(=O)NCC(F)(F)F)cc2I)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)O)nn2)c(I)c1
Yield: 81.3 %

Procedure:
A solution of ethyl 1-(2-iodo-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxylate (3.39 g, 7.24 mmol) obtained in Example 379c) in ethanol (100 ml), 8M aqueous sodium hydroxide solution (7 ml) and water (15 ml) was stirred at room temperature for 18 hr. Ethanol was evaporated under reduced pressure, and the obtained residual aqueous solution was acidified (pH<3) with 6M hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration and washed with water and dried to give the title compound as a pale-yellow powder (2.59 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]([F:38])([F:37])[CH:34]1[CH2:36][O:35]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:36][CH:34]([OH:35])[C:33]([F:38])([F:37])[F:32])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: Cc1cc(Nc2nc(Nc3ccc(C4CCNCC4)c4ccccc34)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccc(C4CCN(CC(O)C(F)(F)F)CC4)c4ccccc34)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine (30.8 mg, 0.07 mmol) and 2-(trifluoromethyl)oxirane (39.2 mg, 0.35 mmol) in 1 mL of DMF was stirred at room temperature overnight. The crude mixture was purified by RP-HPLC to give 3-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1-yl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 546.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(F)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-fluoro-phenyl)-pyridin-3-ol (Preparation 21) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (127 mg, 73.7%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5](O)=[CH:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])[CH3:2].Cl.[NH2:37]O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:11][C:10]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:37]=1)=[O:35])[CH3:2]
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
4-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (1 eq) was dissolved in ethanol with stirring. Hydroxylamine hydrochloride (1.2 eq) was added and the solution was heated to reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between brine and dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br>CN(C)C=O>[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:21][CH:22]=3)[S:13][C:4]1=2
Reactant: Cc1c(-c2ccc(NC(=O)C(C)C)cc2)sc2ncc(C(=O)C(C)C)c(O)c12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(NC(=O)C(C)C)cc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
The compound obtained in Example 28 (1 g), potassium carbonate (0.349 g) and N,N-dimethylformamide (5 ml) were mixed and 2,6-difluorobenzyl bromide (0.783 g) was added and the reaction mixture was stirred at room temperature overnight (15 hours). The reaction mixture was concentrated under reduced pressure to obtain a residue, which was partitioned between ethyl acetate-methyl ethyl ketone and water, and the aqueous layer was extracted with ethylacetate. The organic layers were combined and washed with a saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained after concentration was washed with diisopropylether to obtain the title compound (1.2 g, 91.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26](O)=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:43][CH2:42]3)=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)N2CCN(CC3CCN(C)CC3)CC2)c(C)c1
Reaction time: 2 h

Procedure:
N,N′-Carbonyldiimidazole (131 mg, 0.813 mmol) was added to a solution of (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-acetic acid (step d, Example 127) (325 mg, 0.775 mmol) in dichloromethane (5 ml), and stirring was carried out for 2 h at 30° C. A solution of 1-((1-methylpiperidin-4-yl)methyl)piperazine (152 mg, 0.775 mmol) in dichloromethane (5 ml) was then added at room temperature, and the reaction mixture was stirred for 15 h at that temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added to the mixture, and the aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (40:10:0.5). Yield: 263 mg (57%); MS, m/z 599.3 (MW).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][C:23]([O:25]C)=[O:24])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][C:23]([OH:25])=[O:24])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate (14.84 g, 33.2 mmol), THF (200 ml) and water (120 ml) was a and stirred at room temperature. After 4 h, aqueous NaOH solution (6 M, 60 ml) was again added, and stirring was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure. 6 M HCl solution (125 ml) and DCM (400 ml) were added. After phase separation, the organic phase was washed with saturated NaCl solution, dried (sodium sulfate) and concentrated. For purification, the product was recrystallised from 2-propanol.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[C:39]([CH3:46])[CH:38]=1>C(#N)C>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:3][CH:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][C:16]4=[CH:18][N:19]=[C:20]([CH3:21])[N:15]4[C:14]3=[O:22])[CH2:9][CH2:8]2)=[O:6])=[O:45])=[C:39]([CH3:46])[CH:38]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1NC(=O)NC(C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1)c1ccccc1
Yield: 64.3 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) was dissolved in acetonitrile (5.0 ml). Triethylamine (0.14 ml) and 4-chloro-2-methylphenyl isocyanate (80 mg) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.16 g, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd].C(OC(=O)C)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A round bottom flask was charged with (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (5.0 g, 0.018 mol), palladium on charcoal (10%) (0.3 g, 0.003 mol) and methanol (200 mL, 5 mol) and ethylacetate (80 mL). The reaction mixture was stirred under hydrogen (1 atm) at room temperature for 40 minutes. The mixture was filtered over celite, the solvent was removed to yield the product as a light yellow solid. MS m/z=232.3 (M+H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:30])[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:30][C:4]1[N:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:9][CH:10]=2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)nc(Cl)cc3c2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Temperature: 90 °C
Yield: 741.3 %

Procedure:
This reaction was conducted in two separate vials. For the first reaction, a vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (57.11 mg, 0.109 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (25.1 mg, 0.114 mmol), Pd(AmPhos)2Cl2 (3.85 mg, 5.44 μmol), potassium phosphate (69.3 mg, 0.326 mmol), 1,4-dioxane (408 μl), and water (136 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 15 min at 90° C. A second vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (422 mg, 0.804 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (186 mg, 0.844 mmol), Pd(AmPhos)2Cl2 (28.5 mg, 0.040 mmol), potassium phosphate (512 mg, 2.412 mmol), 1,4-dioxane (3015 μl), and water (1005 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 15 min at 90° C. The reaction mixtures from each vial were combined, and the combined mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chromatography on silica gel (40-g column, 20 to 60% EtOAc/Heptane) to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR; 500.9 mg, 0.808 mmol, 89% yield) as an off-white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.15 (t, J=1.1 Hz, 1H), 7.77 (s, 1H), 7.68-7.65 (m, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J=3.6 Hz, 1H), 6.73 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H); m/z (ESI) 620.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[S:17][C:16]([CH3:18])=[N:15][C:14]=3[C:19](O)=[O:20])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][NH2:31]>>[CH3:18][C:16]1[S:17][C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[C:14]([C:19](=[O:20])[NH:31][CH3:30])[N:15]=1
Reactant: Cc1nc(C(=O)O)c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)s1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1nc(C)sc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1

Procedure:
The product was obtained starting from 5-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-thiazole-4-carboxylic acid (28 mg, 0.07 mmol) and methylamine hydrochloride (6.2 mg, 0.09 mmol) according to the method described in example 64, step 6 as yellow solid (16 mg, 44%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16]CC)=O)[NH:2]1.O.[NH2:20][NH2:21]>CN(C)C=O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([NH:20][NH2:21])=[O:16])[NH:2]1
Reactant: NN
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (4.9 g), hydrazine hydrate (10 ml) and dimethylformamide (50 ml) is allowed to stand at room temperature overnight. The reaction mixture is is distilled under reduced pressure to remove the solvent. The residue is treated with ethyl acetate to give the title compound (3.40 g, 74%) as powder.