Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14](Br)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(NCC)C.[CH3:27][N:28]([CH3:32])[CH2:29][C:30]#[CH:31]>[Cl-].[Cl-].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Pd+2].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:31]#[C:30][CH2:29][N:28]([CH3:32])[CH3:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1CC
Agent: [Pd+2]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCNCC
Product: CCOC(=O)c1ncc2[nH]c3ccc(C#CCN(C)C)cc3c2c1CC
Yield: 48.7 %

Procedure:
347 mg of 6-bromo-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester, 32 mg of palladium-bis-(tri-o-tolylphosphine)-dichloride, 32 mg of cuprous iodide, 5 ml of diethylamine, 5 ml of N-methyl-2-pyrrolidone and 250 mg of 3-dimethylamino-1-propine are heated anhydrously and under nitrogen for 7.5 h at 80°-90° C. After concentration in an oil pump vacuum, the residue is chromatographed on 30 g of silica gel with methylene-chloride/methanol (10/2) as the eluant. The correspondingly consolidated fractions are separated by preparative film chromatography and 170 mg of 6-(3-dimethylamino-1-propinyl)-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].[I:18](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[NH2:1][C:2]1[C:11]([I:18])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(I)c(N)cc1Cl
Reaction time: 18 h

Procedure:
A solution of methyl 4-amino-2-chloro-benzoate (1.14 g, 6.16 mmol) in dichloromethane (30 mL) and methanol (15 mL) was treated sequentially with calcium carbonate (1.85 g, 18.5 mmol) and benzyl trimethylammonium dichloroiodate (3.22 g, 9.24 mmol), stirred for 18 hours, treated with additional benzyl trimethylammonium dichloroiodate (2 g, 5.75 mmol), stirred for 3 days, filtered into a separatory funnel, washed with saturated NaHSO3, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate to provide the majority of the desired product. The filtrate was concentrated, and the concentrate was purified on silica gel with a gradient of from 10% to 20% ethyl acetate/hexanes to provide a total of 1.3 g of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CN)cc1

Procedure:
Intermediate (2d) (5.6 g) was dissolved into 20 mL 30% TFA:DCM and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield the title compound as an oil in a quantitative yield. MS m/z: [M+H+] calcd for C17H21ClN4O4S 413.1. found 413.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>O1CCOCC1>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1CC(CO)C(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Reactant: NCCCN
Solvent: C1COCCO1
Product: NCCCNc1ccc(C2=NNC(=O)CC2CO)cc1[N+](=O)[O-]

Procedure:
14.0 g (50 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-hydroxymethyl-3(2H)-pyridazinone are heated to 60° C. together with 50 ml of 1,3-diaminopropane in 40 ml of dioxane for 8 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1.C[O-].[Na+].CI.[C:26](O)(=O)C>CN(C)C=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:26])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: O=C1CN=C(c2ccc(O)cc2)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a solution of 6.5 g (0.022 mole) of 7-chloro-1,3-dihyro-5-(4-hydroxyphenyl)-2H-1,4-benzodiazepin-2-one in 40 ml of dimethylformamide was added 11.6 ml (0.055 mole) of 4.74 M sodium methoxide in methanol. After 90 min, the mixture was cooled in an ice bath and 9.4 g (0.066 mole) of methyl iodide was added dropwise with stirring. After 18 hr at room temperature the reaction mixture was acidified with acetic acid, and partitioned between 100 ml of dichloromethane and 100 ml of water. The water layer was extracted once more with dichloromethane. The combined dichloromethane extracts were evaporated to dryness. The residual product mixture was separated on a column of Florisil. The column was eluted with dichloromethane, ether and then ethyl acetate. The ethyl acetate fraction was evaporated and crystallized from methanol to give 0.40 g (6%) of product as colorless prisms, mp 225°-259°.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.Cl.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[SH:29].[Cl:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([Cl:40])[C:32]=1[CH2:41][C:42](O)=O>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[S:29][C:42]([CH2:41][C:32]3[C:33]([Cl:40])=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:31]=3[Cl:30])=[N:21][C:22]=2[CH:27]=1
Reactant: O=C(O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: Nc1cc(Cl)ccc1S
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1cc(Cl)c(Cc2nc3cc(Cl)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
By a modification of the procedure of D. L. Boger (J. Org. Chem. 43:2296-2297 (1978)) a solution of P2O5/MeSO3H (Aldrich, 7.5 g, 1:10, w:w) was treated with 2-amino-4-chlorobenzenethiol hydrochloride (Example 6, 1.96 g, 10.0 mmol) and (2,6-dichloro-4-nitrophenyl)-acetic acid (2.50 g, 10.0 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated at 90° C. overnight (15 hours). After cooled to room temperature, the reaction mixture was poured to ice and the resulting mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (CH2Cl2) to yield 3.7 g (99%) of compound 8 as a pale yellow solid. 1H NMR (CDCl3) δ 8.28 (s, 2H), 7.98 (d, J=1.9 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 4.87 (s, 2H). MS (M+H) 373.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH2:19])=[N:17][C:4]=2[CH:3]=1>CCOC(C)=O.[Pt](=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])=[N:17][C:4]=2[CH:3]=1
Reactant: C=C(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (530 mg, 1.07 mmol) in EtOAc (12 mL) was added platinum(IV) oxide (53 mg). The reaction was placed under a H2 atmosphere and stirred for 3 h. The reaction was filtered through celite, washing with MeOH, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluting with 38-50% EtOAc/petroleum ether) to yield 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ES/APCl calcd. for C26H26Cl2FN5 [M+H]+ 498. found 498.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>CS(C)=O.O>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a solution of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone (0.5 g, 2.5 mmol) in dimethylsulfoxide (2.5 mL) and water (1 mL) was added N-bromosuccinimide (0.87 g, 5.0 mmol). The mixture was allowed to stir at room temperature and then was quenched with water (100 mL) to get solid. The solid was collected by filtration and washed with water to give 2-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (450 mg, 64%).
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.[OH-].[Na+].[CH3:34][CH:35]([O:42]S(C1C=CC(C)=CC=1)(=O)=O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)C>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:42][CH:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(OCc2ccccc2)cc1
Yield: 97.3 %

Procedure:
Hydroquinone monobenzyl ether (50 g, 0.25 mol) was added to ethanol (250 ml), followed by adding to the solution, NaOH (12 g, 0.30 mol) and optically active p-toluenesulfonic acid 1-methyl-heptyl ester (78 g, 0.274 mol) prepared in Example 1 with stirring, refluxing the mixture for about 10 hours, distilling off ethanol, adding 6N-HCl (250 ml) and toluene (500 ml) to carry out extraction with toluene, washing the toluene layer with 2N-NaOH aqueous solution, then with water till the washing water became neutral, and distilling off the solvent to obtain optically active p-(1-methyl-heptyloxy)-phenol benzyl ether (76 g). This product (50 g, 0.16 mol) was dissolved in ethanol (100 ml) and reduced in the presence of Pd/C catalyst to obtain optically active p-(1-methylheptyloxy)-phenol (24 g) having a b.p. of 162°-165° C./6 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH3:12])[C:13](=[O:15])[CH:14]=[C:7]2[OH:9]
Reactant: CNc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c(=O)cc(O)c2cc(Cl)ccc21

Procedure:
5-Chloro-N-methyl anthranilic acid (15g; 0.081 mole) was dissolved in acetic acid (41 ml) and acetic anhydride (41 ml) and the dark mixture refluxed for 12 hours. After cooling the red solution was poured onto crushed ice, basified with 2.5N sodium hydroxide and filtered free of tar. The filtrate on acidification to pH5 gave the carbostyril as a yellow solid, m.p. (AcOH) 317°-318° C (Found; C, 57.39; H, 3.98; N, 6.83; Cl, 16.69; C10H8NClO2 requires C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [C:1](OC(C)(C)C)(=O)CC(C)=O.N([O-])=O.[Na+].[OH:16][N:17]=[C:18]([C:26](=[O:28])[CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(O)(=O)C.O.ClCCl>[CH3:1][O:16][N:17]=[C:18]([C:26](=[O:28])[CH3:27])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In 31.6 g of glacial acetic acid was dissolved 31.6 g (0.2 mole) of tert-butyl acetoacetate, and a solution of 15.2 g (0.22 mole) of sodium nitrite in 30 ml of water was added dropwise at 0° to 5° C. over a period of 2 hours and stirred at room temperature for 1 hour. After completion of the reaction, 100 ml of water and 100 ml of dichloromethane were added and then stirred, and the resulting mixture was allowed to stand to be separated and the aqueous layer was removed. To the thus obtained solution of tert-butyl 2-hydroxyimino-3-oxobutyrate in dichloromethane was added 41.5 g (0.3 mole) of potassium carbonate with cooling, after which 27.8 g (0.22 mole) of dimethyl sulfate was added dropwise at 20° C. over a period of 2 hours and stirred at 20° C. for another 1 hour. After completion of the reaction, the reaction solution was washed with 150 ml of water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 38.0 g (yield 95%) of tert-butyl 2-methoxyimino-3-oxobutyrate as a light-yellow, oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CO.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13]([OH:15])([C:34]([F:37])([F:36])[F:35])[CH2:12][CH2:11][N:10]2[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
To a solution of benzyl 2-(3,4-difluorophenyl)-4-oxopiperidine-1-carboxylate (0.21 g, 0.60 mmol) (reagent preparation 20, step 2) in dimethylformamide (4.0 mL) at 0° C. was added cesium carbonate (0.30 g, 0.90 mmol), followed by the addition of trimethyl(trifluoromethyl)silane (0.35 mL, 2.40 mmol). The reaction mixture was stirred at room temperature for 12 hours then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. To a solution of the residue in methanol was added potassium carbonate (0.16 g, 1.19 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate and washed with 1M aqueous hydrochloric acid, brine, dried over anhydrous magnesium sulfate then filtered and concentrated to give benzyl 2-(3,4-difluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (0.24 g, quantitative).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([NH:17]C(=O)C)[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[NH2:17][C:14]1[N:13]=[CH:12][C:11]2[N:10]=[C:9]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[CH:15]=1
Reactant: CC(=O)Nc1cc2c(cn1)nc(-c1cc(C)c(=O)n(C)c1)n2Cc1ccccc1
Agent: Cl
Product: Cc1cc(-c2nc3cnc(N)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-[1-Benzyl-2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1H-imidazo[4,5-c]pyridin-6-yl]-acetamide II-16′ (1.67 g; 4.315 mmol) is suspended in 6 N HCl. The reaction mixture is stirred for 1 h at 100° C. The reaction is then cooled to RT and quenched slowly with sodium bicarbonate, precipitation of the product occurs. The product is filtered off and dried under vacuum.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)O1.[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([C:2]2[S:6][C:5]([NH:7][C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)=[N:4][CH:3]=2)=[CH:28][CH:29]=1)#[N:32]
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CS(=O)(=O)Nc1cccc(Nc2ncc(Br)s2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)s2)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
To a mixture of N-(3-((5-bromothiazol-2-yl)amino)phenyl)methanesulfonamide 56 (0.159 g, 0.458 mmol), commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 57 (0.125 g, 0.545 mmol), Lithium chloride (0.038 g, 0.916 mmol) and tetrakis(triphenylphosphine)palladium (0.058 g, 0.05 mmol) in dry and degassed (using argon) 1,4-Dioxane (20 mL) was added aq. Na2CO3 (1M, 0.91 mL, 0.916 mmol). Reaction mixture was degassed again for 2-3 times for 10 minutes and resulting yellow mixture was stirred under argon at 100° C. for 14 hours. Reaction mixture was filtered through a small pad of celite and concentrated. Crude product was MPLC (Biotage) silica column chromatographed using Acetone:Hexane as an eluent to obtain N-(3-((5-(4-cyanophenyl)thiazol-2-yl)amino)phenyl)methanesulfonamide 58 (0.15 g, 89% yield). MS (ES) m/z 371 (M+H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.C(C1C=CC([Mg]Br)=CC=1)C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:11]3[CH:10]=[CH:9][C:14]([CH2:15][CH3:6])=[CH:13][CH:12]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-ethylphenylmagnesium bromide. Yield: 80 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[C:23]([O:25]CC)=[O:24])[S:17][CH:18]=2)[S:12][CH:13]=1)=[O:8].[Li+].[OH-]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[C:23]([OH:25])=[O:24])[S:17][CH:18]=2)[S:12][CH:13]=1)=[O:8]
Reactant: CCOC(=O)C(=O)NCCc1nc(-c2nc(C(=O)NCCCSC)cs2)cs1
Agent: [Li+]
Agent: [OH-]
Product: CSCCCNC(=O)c1csc(-c2csc(CCNC(=O)C(=O)O)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 118 (12.7 mg, 0.029 mmol) in THF-H2O--CH3OH (3:1:1, 0.45 mL) was treated with LiOH (6.0 mg, 0.14 mmol, 5.0 equiv) and the mixture was stirred at 25° C. for 2 h before the solvent was removed in vacuo. The crude product was dissolved in H2O and was acidified to pH 0.5 with the addition of 10% aqueous HCl. The product was extracted with 30% isopropanol-CHCl3 (7×1.2 mL), and the combined extracts were concentrated to afford 119 (11.9 mg, 11.9 mg theoretical, 100%) as an off white solid which was sufficiently pure to use in the next reaction directly: 1H NMR (CD3OD, 400 MHz) 8.16 (s, 1H), 8.14 (s, 1H), 3.71 (t, J=6.8 Hz, 2H), 3.51 (t, J=7.0 Hz, 2H), 3.30 (t, 2H, overlapped with CH3OH), 2.58 (t, J=7.2 Hz, 2H), 2.10 (s, 3H), 1.92 (tt, J=7.2, 7.0 Hz, 2H); IR (film)max 3346, 3102, 2916, 1656, 1543, 1480, 1436, 1362, 1294, 1240, 1128, 1054 cm-1 ; FABHRMS (NBA) m/z (M++H, C15H18N4O4S3 requires 415.0568).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]2)=[O:45]>CS(C)=O>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:57])[F:58])[CH2:49]3)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: CS(C)=O
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2

Procedure:
5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-iso indol-5-yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b from 1.38 g (6.80 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 2.08 g (7.14 mmol) 1-[5-(2-chloro-acetyl)-1,3-dihydroisoindol-2-yl]-2,2,2-trifluoro-ethanone (see preparation 23) in DMSO as solvent (purification via reversed HPLC chromatography).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[I:12][C:11]1[C:4]2[C:3]([NH2:1])=[N:8][CH:7]=[N:6][C:5]=2[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1
Reactant: N
Reactant: Clc1ncnc2c1c(I)cn2-c1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2-c1ccccc1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.084 mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=5.69 (brs, 2H), 7.36 (s, 1H), 7.36-7.41 (m, 1H), 7.49-7.55 (m, 2H), 7.60-7.64 (m, 2H), 8.33 (s, 1H). MS (ES+): m/z 337.0 (100) [MH+]. HPLC: tR=2.8 min (OpenLynx, polar—5 min).