Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.ClC1C=C(C(F)(F)F)C=CN=1>>[CH3:8][C:4]([O:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)([CH3:9])[C:5]([OH:7])=[O:6]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(O)C(=O)O
Agent: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Reference Example 36, Step A with 1.5 extra equivalent of sodium hydride substituting lithium lactate with hydroxyisobutyric acid and 2-chloro-4-trifluoromethylpyridine 2-chloro-5-trifluoromethylpyridine. 1H NMR (500 MHz, CD3OD): δ 8.38 (br, 1H), 7.94 (dd, 1H), 6.93 (d, 1H), 1.69 (s, 6H).
Reaction SMILES: C([N:11]([C:28]1[CH:29]=[C:30]([C:33](Cl)=[O:34])[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:43]([OH:51])(=[O:50])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45].[H][H]>O1CCCC1.[Pd].CCOCC>[CH2:12]([NH:11][C:28]1[CH:29]=[C:30]([C:33]([O:50][C:43](=[O:51])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45])=[O:34])[S:31][CH:32]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1csc(C(=O)Cl)c1
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(=O)C(O)CC(=O)O)c1

Procedure:
A warm solution of 4-[N-(carbobenzyloxy)-N-(hexadecyl)amino]-2-thiophenecarbonyl chloride and 1.3 g. of triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether; then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, and the solution is evaporated. The residue is crystallized from acetic acid to yield the product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][C:28](Cl)=[O:29]>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH:13][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(Cl)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
3,4-dibenzyloxybenzylamine (1.1 g, 3.45 mmol) was dissolved in anhydrous pyridine (8 ml) and cooled to 0° C. with stirring under nitrogen. To this solution, succinyl chloride (0.23 g, 1.42 mmol) was added dropwise over 30 minutes as a solution in dichloromethane (50 ml), while maintaining the reaction mixture at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 45 minutes. The reaction was poured onto crushed ice (70 g) and the dichloromethane layer was separated. The organic extract was washed with dilute aqueous hydrochloric acid (2×20 ml of 0.1M solution), water (20 ml), and dried (Na2SO4). Removal of the solvent at reduced pressure afforded a crude solid, which was triturated with methanol (5 ml) to afford after filtration the protected diamide, yield 300 mg.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1CCCCC1)C=2)=O)CCC.P(Br)(Br)([Br:55])=O>C(#N)C>[Br:55][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:5])=[O:7])[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Agent: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Solvent: CC#N
Product: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 8 h

Procedure:
1,4-Dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (Example A-63 d) Compound A) (29.0 g) and phosphorous oxybromide (67.5 g) in 600 ml anhydrous acetonitrile was stirred at reflux for 4 hours. After cooling the reaction mixture was concentrated and saturated sodium bicarbonate solution and ethyl acetate were added to the residue and stirred overnight. Precipitate that formed between layers was collected and washed with water to give the title compound (10.2 g). MS-(+)-ion M+1=376.0, 378.1.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 99.3 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-cyclopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (740 mg, 2.53 mmol) was reduced with hydrogen and 10% Pd/C (350 mg) to form the desired product (660 mg, 99%). 1H NMR (MeOD-d4): δ 6.83 (m, 2H), 2.20 (m, 1H), 0.56 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:24]=3[C:25]([F:28])([F:27])[F:26])=[C:15]1[CH2:14][CH2:13]2)[C:3]([O:5]CC)=[O:4].[OH-:39].[Na+].[CH3:41][OH:42]>>[NH2:1][C@@:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:24]=3[C:25]([F:26])([F:28])[F:27])=[C:15]1[CH2:14][CH2:13]2)[C:3]([OH:5])=[O:4].[C:41]([OH:42])([C:25]([F:28])([F:27])[F:26])=[O:39]
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)C(C)(N)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: [Na+]
Product: C[C@](N)(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)C(=O)O
Product: O=C(O)C(F)(F)F
Yield: 63.1 %

Procedure:
A solution of ethyl 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50D, 4 mg, 7.63 μmol) and 10% aqueous sodium hydroxide (0.2 mL) in methanol (0.2 mL) was stirred under nitrogen at 60° C. for 1.5 hr and then room temperature overnight. Purification using reverse phase HPLC (PHENOMENEX® Luna Axia 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, and lyophilization gave (2S)-2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoic acid, TFA (3 mg, 4.82 μmol, 63.1% yield) as a white solid. The compound had an HPLC retention time=3.07 min (condition C); LC/MS M+1=497.3; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.86 (1H, d, J=7.7 Hz), 7.54-7.64 (5H, m), 7.22-7.30 (2H, m), 3.03 (2H, t, J=7.0 Hz), 2.90 (2H, t, J=7.0 Hz), 2.83 (1H, td, J=13.1, 5.0 Hz), 2.65 (1H, td, J=13.0, 5.0 Hz), 2.26 (1H, td, J=13.5, 4.7 Hz), 2.10 (1H, td, J=13.5, 4.7 Hz), 1.62 (3H, s).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH2:7])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>O1CCCC1>[CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C1CC(CN)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
Compound 4-2 (3 g, 30.9 mmol) was dissolved in 50 mL of tetrahydrofuran, added Na2CO3 (6.3 g, 60 mmol) and benzyl chloroformate (5.25 g, 30.8 mmol). The mixture was stirred for 12 hours at room temperature, added 100 mL of water, extracted three times with 300 mL of ethyl acetate, combined the organic phases, rotary evaporated to remove solvents and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 4-3 (4 g, 56% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])#[N:2].N>CO.[Ni].CCO>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(C#N)c(N(C)S(C)(=O)=O)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: Cc1ccc(CN)c(N(C)S(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(2-cyano-5-methyl-phenyl)-N-methyl-methanesulphonamide (B-1a) (10.0 g, 44.6 mmol) is dissolved in 60 mL MeOH and 20 mL methanolic ammonia (7 M) in a hydrogenating autoclave and combined with Raney nickel in EtOH (1 g). The reaction mixture is then hydrogenated at 3 bar H2 and 80° C. for 16 h. After the reaction has ended the reaction mixture is filtered and the filtrate is mixed with ethanolic HCl (4.5 mL, 10 M). The precipitate formed is filtered off and the solid B-2a (HPLC-MS: tRet.=1.03 min; MS (M+H)+=229) is used without any further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:4]([CH3:18])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(I)ccc1CCCN1CCC(C)CC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCCN1CCC(C)CC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[3-(4-iodo-2-methylphenyl)propyl]-4-methylpiperidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 29 mg (9% of theoretical); C29H31ClN2 (M=443.023); calc.: molpeak (M+H)+: 443/445 (Cl); found: molpeak (M+H)+: 443/445 (Cl); HPLC-MS: 8.55 minutes (method A).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[NH2:20]CC(O)=O>C(OCC)(=O)C>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([NH2:20])=[O:3])=[CH:5][C:6]1=2
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Reflux 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxodibenz[b,e]oxepin in 20 cc of ethyl acetate containing 2.0 gm of glycine for 5 hours. Evaporate the mixture to dryness. Add 30 cc of water to the solid residue and stir at room temperature for one hour. Separate the solid by filtration and recrystallize from ethanol to obtain the title product.
Reaction SMILES: CCOCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20](=[O:24])[C:21](Cl)=[O:22].[C:25]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:25]([CH:33]1[CH2:38][CH2:37][N:36]([C:21](=[O:22])[C:20]([C:11]2[C:10]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:8]([O:7][CH3:6])[CH:9]=3)[NH:13][C:12]=2[CH3:19])=[O:24])[CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: COc1cc2[nH]c(C)c(C(=O)C(=O)Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)N3CCC(C(=O)c4ccccc4)CC3)c2cc1OC

Procedure:
The above ether suspension of 5,6-dimethoxy-2-methyl-3-indoleglyoxylyl chloride is added portionwise to a cooled stirring mixture of 4benzoylpiperidine [Example 9(a)], 150 ml of water, 150 ml of chloroform and 25 g of potassium carbonate. The mixture is stirred for 16 hours at ambient temperature, the organic layer is separated and the solvent is removed, leaving a brown oil which is triturated with cyclohexane and then stirred for 16 hours with ether. A white solid results which is collected, dried and recrystallized thrice from methanol to give the compound, mp 188°-190° C., 4-benzoyl-1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(CO)[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: OCC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCC4)c(Cl)c3)c2cc1OC
Yield: 68.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopentylmethanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (47 mg, yield 59%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18][N:17]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[CH:16]4)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc2cnccc12
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cnccc23)cc1=O
Yield: 73 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and isoquinolin-5-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(isoquinolin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.1 g, 73%) as a brown solid; ESI-MS 380 [M+H+]; HPLC: >96% (purity). 1H-NMR (300 MHz, DMSO-d6): δ 1.11 (m, 2H), 1.52 (m, 7H), 2.01 (m, 1H), 2.22 (m, 1H), 5.32 (m, 1H), 5.89 (s, 1H), 7.77 (m, 3H), 8.14 (m, 1H), 8.27 (m, 1H), 8.59 (m, 1H), 9.46 (s, 1H), 13.00 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:40][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCCC1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Product: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 100 °C
Yield: 27.2 %

Procedure:
A solution of 98 mg of [4-(5-methanesulfonyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester, 19 mg of cyclopentanol and 69 mg of (tert-butylimino)tris(pyrrolidino)phosphorane was reacted at room temperature for 16 h and subsequently heated in a microwave reactor to 100° C. for 10 min. The mixture was poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with a 10% aqueous solution of citric acid and brine, dried and evaporated. After purification by preparative HPLC, 27 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH2:26]([O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31])[CH3:27].[OH-].[Na+].Cl>CC(N(C)C)=O>[CH2:26]([O:28][C:29](=[O:34])[C:30]([O:9][C:6]1[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]2[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=1[Cl:8])([CH3:32])[CH3:31])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 46.2 %

Procedure:
5-[2-(2,3-Dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 197, step 5; 198 mg, 0.50 mmol) and 2-bromo-2-methyl-propionic acid ethyl ester (0.23 mL, 1.5 mmol), were dissolved in 1 ml dimethylacetamide and treated with 60 mg NaOH (finely powdered). After 3 h stirring at rt 2-bromo-2-methyl-propionic acid ethyl ester (0.11 mL, 0.75 mmol) was added, followed by 30 mg NaOH (finely powdered). After 19 h stirring at rt, the reaction mixture was poured on ice-water (10 mL) and the pH adjusted to 3 with aqueous 2N HCl. The reaction mixture was then extracted twice with ethyl acetate, the combined organic phases washed with water and brine, dried over magnesium sulfate, filtered-off and concentrated in vacuo. The residue was purified by flash chromatography (8 g SiO2, EtOAc/heptane 2:1) to give 118 mg of the title compound as colorless viscous oil. MS (M+H+)=510.2
Reaction SMILES: [OH:1][C:2]1[C:3]([C:21]([O:23]C)=O)=[N:4][N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:7](=[O:20])[C:6]=12.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][C:21]([C:3]1[C:2]([OH:1])=[C:6]2[C:7](=[O:20])[N:8]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[CH2:9][CH2:10][N:5]2[N:4]=1)=[O:23]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1nn2c(c1O)C(=O)N(CC(=O)N1CCOCC1)CC2
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nn2c(c1O)C(=O)N(CC(=O)N1CCOCC1)CC2
Temperature: 90 °C

Procedure:
Methyl 3-hydroxy-5-[(2-morpholin-4-yl)-2-oxoethyl]-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (15 mg, 0.044 mmol) was dissolved in 3,4-dichlorobenzylamine (1.5 mL) and heated to 90° C. for 30 minutes. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, d6-DMSO) δ 8.89-8.86 (t, 1H), 7.55-7.51 (m, 2H), 7.27-7.25 (d, 1H), 4.40-4.38 (d, 2H), 4.33-4.29 (m, 4H), 3.84 (br s, 1H), 3.74-3.71 (t, 2H), 3.58-3.52 (m, 4H), 3.42-3.39 (m, 4H); ES MS (M+1)=482.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>COC(C)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
4-Chloroaniline (52.7 kg, 413 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15° C. To the resulting slurry was charged trimethylacetyl chloride (52.2 kg, 448 mol) over 1 h, keeping the temperature below 40° C. After stirring 30 min at 30° C. the slurry was cooled to -10° C. and held for 2 hours. The product was collected by filtration, washed with a solution of 90/10 water/methanol (175 kg), then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153° C.; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=9 Hz, 2H) 7.28 (d, J=9 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])=O)[CH3:10].[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28])[CH3:23]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])=[C:27]([CH3:28])[NH:29][C:14]=1[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[O:21])[CH3:10]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)CC(=O)COC(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccn1
Yield: 60 %

Procedure:
A solution of 5.4 g of pyridine-2-aldehyde, 9.4 g of γ-acetoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol is heated to the boil overnight and then cooled. After filtering, beige crystals of melting point 116° C. are obtained, yield: 60%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([SH:8])[CH:7]=1.[Cl:11][C:12]([CH2:14]Cl)=[CH2:13]>CN(C)C=O>[Cl:9][C:5]1[C:6]([S:8][CH2:14][C:12]([Cl:11])=[CH2:13])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(S)c(Cl)cc1F
Reactant: C=C(Cl)CCl
Solvent: CN(C)C=O
Product: C=C(Cl)CSc1cc(N)c(F)cc1Cl
Yield: 83.2 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorothiophenol (8.89 g) and anhydride potassium carbonate (3.5 g) was dissolved in N,N-dimethylformamide (100 ml), and 2,3-dichloropropene (6.65 g) was added thereto. The resultant mixture was stirred at 20° to 40° C. for 4 hours. After completion of the reaction, the reaction mixture was extracted with ether,washed with water, dried and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/1) to give 4-chloro-2-fluoro-5-(2-chloro-2-propenylthio)aniline (10.5 g; yield, 84%).