Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]N1C(=O)CCC1=O.O[CH2:29][C:30]1[O:35][CH2:34][N:33]([C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32](=[O:46])[C:31]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[Cl:20][CH2:29][C:30]1[O:35][CH2:34][N:33]([C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32](=[O:46])[C:31]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N1COC(CO)=C(c2ccccc2)C1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)N1COC(CCl)=C(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A solution of triphenylphosphine (1.82 g) in tetrahydrofuran was added dropwise to a stirred solution of N-chlorosuccinimide (1.08 g) in tetrahydrofuran. After 10 minutes a solution of tert butyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.0 g) in tetrahydrofuran was added. The mixture was stirred overnight and partitioned between ether and water, and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethanelhexane (2:1) to give tert butyl 2-(6-chloromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.49 g) as a white solid, m.p. 128-129° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.72 min; [M+H]+=407.20.
Reaction SMILES: [NH:1]1[C:6]2=[N:7][C:8]([CH:11]=O)=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:20]([NH2:23])([CH3:22])[CH3:21].C(O)(=O)C>ClCCl>[CH3:21][CH:20]([NH:23][CH2:11][C:8]1[N:7]=[C:6]2[NH:1][CH2:2][CH2:3][CH2:4][C:5]2=[CH:10][CH:9]=1)[CH3:22]
Reactant: CC(C)N
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)NCc1ccc2c(n1)NCCC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydropyridino[2,3-b]pyridine-7-carbaldehyde in dry dichloromethane (32 mL) were added 4° A seives, sodium sulfate and isopropyl amine. The mixture was cooled to 0° C. followed by the addition of acetic acid (300 μL). The resulting mixture was stirred at room temperature under nitrogen for 18 hrs. The mixture was filtered through celite, diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, evaporated concentrated in vacuo and purified by flash chromatography(10% MeOH/CH2Cl2 ). EI-MS m/z 206 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl>CO.Cl>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([NH2:10])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1cc(F)c(Br)cc1F

Procedure:
To a solution of 2,5-difluoro-4-bromo-nitrobenzene (10 g, 42 mmol) in MeOH (200 mL) and conc. HCl (11 mL) was added tin(II)chloride dihydrate (38 g, 168 mmol) at room temperature. When complete the MeOH was distilled off under vacuum then water and celite were added. The mixture was neutralized with NaOH (50%) and filtered to remove the tin residue. The mixture was extracted with CH2Cl2 and the title compound 468A crystallized from CH2Cl2/hexane.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([O-:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-methylthiazole-5-carboxylate in a mixture of tetrahydrofuran and water (2/1) is added lithium hydroxide monohydrate (6.9 equivalents) at ambient temperature. The reaction mixture is stirred at ambient temperature for 17 h and concentrated in vacuo. The residue is acidified by the addition of 4 M hydrochloric acid solution to pH ˜3. The solid is collected by filtration, washed with water and hexane, and dried in vacuo to afford the title compound.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[C:23]([OH:24])=[C:22]2[C:17]([CH:18]=[N:19][C:20]([Cl:25])=[N:21]2)=[CH:16][CH:15]=1.O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][C:14]1[C:23]([O:24][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[C:22]2[C:17]([CH:18]=[N:19][C:20]([Cl:25])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1c(Br)ccc2cnc(Cl)nc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of DEAD (404 mg, 2.32 mmole) in THF (0.5 mL) was added to a solution of 7-bromo-2-chloroquinazolin-8-ol (400 mg, 1.54 mmole), tert-butyl 4-hydroxypiperidine-1-carboxylate (621 mg, 3.09 mmole) and PPh3 (610 mg, 2.32 mmole) in THF (5.5 mL) at RT. After 1.5 hours, silica gel was added to the reaction which was evaporated to dryness and loaded onto a flash column. The product was eluted with 25% EtOAc/hexane to give tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate in 80% yield (545 mg, 1.23 mmole).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Reaction time: 1 h

Procedure:
1.79 g of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in Preparation 8) was dissolved in 15 ml of anhydrous dimethylformamide. 0.35 g of a 55% w/w suspension of sodium hydride in mineral oil was added, and the solution was stirred for 1 hour. To this solution, was added, whilst ice-cooling, 1 ml of a dimethylformamide solution containing 1.34 g of ethyl bromoacetate, and the mixture was stirred for 1 hour at room temperature and then for 3 hours at 80° C. At the end of this time, the dimethylforamide was distilled off under reduced pressure and the mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to dryness. The addition of hexane precipitated 1.85 g of the title compound as white needles melting at 134°-136° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.CO.[OH-].[Na+]>C1COCC1>[C:31]([O:30][C:28]([N:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][N:7]=2)=[CH:17][CH:16]=1)[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1ccc(Oc2ccc(CN(CCc3ccccc3)C(=O)OC(C)(C)C)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Combine 6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinic acid ethyl ester (0.333 g, 0.72 mmol), MeOH (5 mL), THF (5 mL), and 2.5N NaOH (aq) (2 mL). After the reaction refluxes under a Nitrogen atmosphere for 24 hours, concentrate under reduced pressure. Add 2.5N HCl (aq) (2 mL), Ethyl acetate, and wash with water, brine, and then dry over Na2SO4. Concentrate the organic mixture under reduced pressure to afford 293.0 mg (91% yield) of title compound as a white foam: 1H NMR (500 MHz, CDCl3); 1.4 (9H, s), 2.6-2.8 (2H, m), 3.2-3.4 (2H, m), 4.2-4.4 (2H, m), 4.3-4.4 (2H, m), 6.9 (1H, d), 7.0-7.3 (9H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 349 (M−100, Boc).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH:13][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OC(C)CN)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCC(C)Oc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenoxy]propylamine (1.13 g, 5.10 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (1.16 g, 10.60 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.4 ml). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)phenoxy]propyl}carbamate.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH:36][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=2[NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.97 min. MS (ESI+): mass calcd. for C24H19Cl2IN4O3S, 639.96; m/z found, 641/643 [M+H]+; m/z found, 663/665 [M+Na]+. 1H NMR (400 MHz, CDCl3): 11.07 (s, 1H), 9.03 (d, J=1.8, 1H), 8.95 (d, J=1.8, 1H), 8.56 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4, 1H), 8.05 (d, J=1.6, 1H), 7.91-7.87 (m, 1H), 7.39 (d, J=8.2, 1H), 7.28-7.24 (m, 2H), 7.02 (dd, J=8.3, 2.1, 1H), 6.75 (d, J=8.2, 1H), 5.81 (s, 1H), 3.68-3.61 (m, 1H), 3.31-3.24 (m, 1H), 3.00-2.95 (m, 1H), 1.29 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C1(C)C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][NH:40][C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: COCCN
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCNC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
A suspension of 0.15 mg (0.35 mmol) of 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 4 ml of toluene was heated at 50° C. for 4 hours with 0.15 ml (2.1 mmol) of thionyl chloride. After removal of all volatile constituents by distillation the residue was suspended in 5 ml of dioxan, treated with 0.06 g (0.76 mmol) of 2-methoxy-ethylamine and stirred at room temperature for 4 hours. After concentration the residue was taken up in dichloromethane, extracted with water and dried with sodium sulphate. Concentration and washing of the residue with ether gave 0.14 g (74%) of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-amide as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15](C5C=CC=CN=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:44](O)([C:46](F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:12]5[CH:13]=[N:14][CH:9]=[CH:44][CH:46]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccn3)CO4)cc2)CCC1
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3cccnc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 56 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(pyridin-2-yl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (8 mg, 56% yield). LCMS (Method A) RT=3.73 min, M+1=474. 1H NMR (500 MHz, CDCl3): 8.99 (1H, d), 8.86 (1H, dd), 8.30 (1H, dt), 7.75 (1H, dd), 7.48 (2H, d), 7.42 (2H, d), 7.37 (1H, s), 7.31-7.20 (3H, m), 7.01 (2H, d), 5.78 (2H, s), 2.83-2.72 (2H, m), 2.63-2.54 (2H, m), 2.30-2.17 (1H, m), 2.05-1.90 (1H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (28.3% yield). 1H NMR (400 MHz, CDCl3) δ8.05, 7.86, 7.78-7.75, 7.28-7.22, 7.12-7.08, 7.02, 4.08-4.01, 3.91-3.86, 3.82-3.68, 3.55-3.46, 3.38, 1.73-1.65, 1.56-1.48, 0.94.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH2:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1.O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]([C:24](=[O:25])[C:19]2[S:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A solution of 667 mg (2.5 mmole) of N-t-butyl-6-chloro-2-oxindole-1-carboxamide and 684 mg (5.6 mmole) of 4-(N,N-dimethylamino)pyridine in 8 ml of N,N-dimethylformamide was cooled in an ice-bath, and then a solution of 410 mg (2.8 mmole) of 2-thenoyl chloride in 2 ml of N,N-dimethylformamide was added dropwise, with stirring. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 60 ml of water and 2.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and then the solid was recovered by filtration and recrystallized from ca. 30 ml of acetic acid. This afforded 425 mg of the title compound as yellow crystals, mp 160.5°-161.5° C. (slight decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (33; 7.56 mmol, 1.0 g) was taken up in 20 mL of dichloromethane. Triethylamine (26.46 mmol, 3.687 mL) was then added, followed by p-toluensulfonyl chloride (15.12 mmol, 2.88 g) and catalytic amount of 4-dimethylamino pyridine. The reaction was allowed to stir at room temperature for 18 h. The crude reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium bicarbonate solution, water, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue 34 was used for the next step without further purification (89% crude yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13](=[O:14])[N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH:7]3[C:6]=2[N:15]=1.CCN(C(C)C)C(C)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([N:11]2[CH2:10][CH2:9][N:8]3[C:13](=[O:14])[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[N:15][C:6]=4[CH:7]3[CH2:12]2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH3:26]
Reactant: Cc1ccc2c(n1)C1CNCCN1C2=O
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a suspension of 2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as described in Intermediate 8; 70 mg) in DCM (5 mL) was added DIPEA (0.241 mL, 1.378 mmol). To this was added 4-(ethyloxy)benzenesulfonyl chloride (80 mg) and this was allowed to stir at room temperature for 30 minutes. The reaction mixture was partitioned between DCM and saturated sodium bicarbonate solution in a hydrophobic frit. The aqueous layer was re-extracted with DCM. The combined organic phases were evaporated to an orange oil. The residue was purified by chromatography (25S silica cartridge) eluting with 0-5% methanol in DCM over 12 column volumes. The clean fractions were combined and evaporated to give the title compound as a white foam (84 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:14]2[S:13][C:12]([Cl:15])=[N:11][C:10]=2[C:9]([Cl:16])=[CH:8][C:7]=1[Cl:17]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[S:13][C:14]2[C:6]([N:5]=[C:1]=[O:2])=[C:7]([Cl:17])[CH:8]=[C:9]([Cl:16])[C:10]=2[N:11]=1
Reactant: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C=Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere 25 mL of ethyl acetate was stirred and cooled in an ice bath. To this was added via syringe 9.5 mL (18 mmole) of 1.9M phosgene in toluene. During 25 minutes, a solution of 3.0 grams (11.8 mmole) of 7-amino-2,4,6-trichlorobenzothiazole in 75 mL of ethyl acetate was added dropwise. Upon completion of the addition the reaction mixture was warmed to ambient temperature and then gently heated at reflux for 2.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding (2,4,6-trichlorobenzothiazol-7-yl)isocyanate, which was stored in a refrigerator.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[Na].[OH2:24]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)[OH:24])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1.1 g of 5-(4-chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 15 ml of ethyl alcohol at 0° C. was added potionwise 0.06 g of sodium borohrdride. After 30 minutes, the rection mixture was poured into iced water and extracted with chloroform, the chloroform solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with n-hexane to afford 1.0 g of 5-(4-chloro-α-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:33]([O:35]C)=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.CO>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:33]([OH:35])=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(CCC)c1
Yield: 50 %

Procedure:
This compound was prepared from the product of Step A by the same procedure as for Example 7, Step E. After chromatographic purification, a 50% yield of the title compound was obtained, homogeneous on TLC (9:1 CH2Cl2 /MeOH).