Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[N:31][OH:32])[NH2:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:30][C:44](=[O:45])[O:32][N:31]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2noc(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 385 mg (0.81 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide (Example 82, Step C) in dioxane (12.5 mL) was added 211 μL (1.41 mmol) of DBU and 262 mg (1.62 mmol) of 1,1′-carbonyldiimidazole. The resulting colorless solution was heated at 100° C. for 25 min, and then was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, and then was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55% MeCN in water to 80% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:27]=3)=[CH:21][N:20]([S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:17]2=[N:18][CH:19]=1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:27]=3)=[CH:21][N:20]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=3)(=[O:38])=[O:37])[C:17]2=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4F)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4F)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(2-fluoro-4-(piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg. 0.192 mmol) was alkylated using (S)-2-methyloxirane (17 mg, 0.288 mmol), DIPEA (75 mg, 0.576 mmol) and ethanol (3 mL) to get 100 mg (76.3%) of the titled compound. MS: m/z=683.2 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([C:39]([O:41][CH3:42])=[O:40])[N:32]=[CH:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([C:39]([O:41][CH3:42])=[O:40])[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: COC(=O)c1ncn(CCCc2ccc(OCc3coc(/C=C/c4ccccc4)n3)cc2)c1C(=O)OC
Yield: 63 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with dimethyl 4,5-imidazoledicarboxylate to give dimethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxylate. The yield was 63%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 85-86° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O>>[OH:8][C:7]1[C:6]2[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][S:3][C:2]=2[N:1]=[CH:17][N:19]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(-c2ccco2)csc1N
Product: Oc1ncnc2scc(-c3ccco3)c12
Temperature: 200 °C
Yield: 52.5 %

Procedure:
A mixture of ethyl 2-amino-4-(2-furyl)thiophene-3-carboxylate (1.00 g, 4.21 mmol) and formamide (10.0 g, 0.2 mol) was warmed by microwave at 200° C. for 10 minutes. The mixture was concentrated in vacuo at 90° C., diluted with 40 mL of 10% methanol/dichloromethane, and filtered through a 40 gram silica gel column using 5% methanol/dichloromethane to wash the material through the column. The filtrate was again concentrated and the remaining residue was purified by column chromatography over silica gel using a gradient elution from 5 to 10% methanol in dichloromethane to give 0.482 g (52.4%) of 4-hydroxy-5-(2-furyl)thieno[2,3-d]pyrimidine as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33](Br)(Br)([Br:35])[Br:34].O>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:33]([Br:35])[Br:34])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(C=C(Br)Br)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
Ethyl-4-formylbenzoate (2.46 g) (ex Lancaster) in dichloromethane (30 ml) under nitrogen was treated with triphenylphosphine (15.7 g) and carbon tetrabromide (9.9 g) at 0°. After 1.5 hours at 25°, water was added and the mixture worked up in the normal manner. Purification by chromatography (silica, ether/hexane) gave ethyl-4-(2,2-dibromoethenyl)benzoate (3.32 g). NMR 1H 8.0(2H,d), 7.50(2H,d), 7.45(1H,s), 3.85(3H,s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:11][N:5]1[CH:6]=[C:7]([C:8]([Cl:17])=[O:9])[C:3]([C:2]([F:13])([F:12])[F:1])=[N:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To 3-(Trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (3.00 g, 15.5 mmol) suspended in dichloromethane was added oxalyl chloride (2.24 g, 17.8 mmol) and dimethylformamide (one drop). The reaction mixture was stirred at room temperature until bubbling stopped at which point the organic solution was evaporated in vacuo to obtain 3.25 g (99%) of the title compound.
Reaction SMILES: Br[O-].[Na+].BrBr.[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:15]=2)[CH:10]=1)(=[O:8])C.S(S([O-])=O)([O-])(=O)=[O:25].[Na+].[Na+]>O.O1CCOCC1>[CH2:22]([S:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:25])[CH:18]=[CH:17]2)(=[O:21])=[O:20])[CH3:23]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CCS(=O)(=O)c1ccc2cc(C(C)=O)ccc2c1
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 5 °C
Yield: 94.3 %

Procedure:
There is prepared in a first stage a solution of sodium hypobromite by adding, at 0° C., 3 cm3 of bromine to a stirred solution containing 7.5 g of soda in 35 cm3 of water. Then, there is slowly introduced a suspension of 1 g of 2-acetyl-6-ethylsulfonyl naphthalene dispersed in 20 cm3 of dioxan in a fashion to maintain the temperature of the reaction mixture lower than 5° C. At the end of the addition, this temperature is again maintained for 1 hour and then there are slowly added at ambient temperature 15 g of sodium metabisulfite dissolved in 150 cm3 of water. On acidifying the mixture with HCl, the anticipated acid precipitates. It is filtered, washed thoroughly with water and dried. 0.95 g of 6-ethylsulfonyl-2-naphthalene carboxylic acid in the form of a white powder whose melting point is 241° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[C:21](=O)[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14]2)([F:12])[CH:6]2[C:10]=1[O:9][CH:8]([CH3:11])[CH2:7]2.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Cl:25][C:21]1[N:13]([C:5]2([F:12])[CH:6]3[CH2:7][CH:8]([CH3:11])[O:9][C:10]3=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][CH2:17][CH2:16]2
Reactant: CC1CC2C(=C(Cl)C=CC2(F)n2[nH]c3c(c2=O)CCCC3)O1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CC1CC2C(=C(Cl)C=CC2(F)n2nc3c(c2Cl)CCCC3)O1

Procedure:
0.25 g of 39C was mixed with 0.14 g of phosphorous oxychloride and 0.15 g of N,N-diethylaniline and heated under nitrogen at 135°-140° C. for three hours, cooled, and diluted with ethyl acetate. The organic phase was washed with water, 10% hydrochloric acid, saturated sodium bicarbonate solution, brine, dried (MgSO4) and stripped of solvent. The residue was purified by flash chromatography on silica gel, using a 1:4 v:v mixture of ether and hexane as eluent to afford the title compound as a yellow glass.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:22]([CH3:31])=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[C:22]([CH3:31])=[C:23]([S:27]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.074 g) as an off-white solid (0.113 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(CCNC(=O)Cc2ccc(C)cc2)cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(C)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
One gram (1.0 g) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methylphenyl) acetamide (3.2 mmol), 1.68 g (9.64 mmol) of t-butoxybis(dimethylamino)methane and 15 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.20 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:10]([C:7]3[CH2:8][CH:9]4[N:4]([CH2:3][CH2:2][CH2:1]4)[CH2:5][CH:6]=3)=[CH:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-7-azaindole (10.2 mg, 58.9%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 4-fluorobenzenesulfonyl chloride (20 mg, 0.095 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Fc1ccc(Br)nc1
Product: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 2-bromo-5-fluoropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d6) δ 13.12 (br. s., 1 H), 8.28 (d, 1 H), 7.78 (d, 1 H), 7.69 (d, 1 H), 7.56 (t, 1 H), 7.48-7.54 (m, 2 H), 7.39 (dd, 1 H)
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:10]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CCCc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
500 mg (3.65 mmol) of the product from example 51A are dissolved in 7.3 ml of DMF and cooled to 0° C. To this are added 613 mg (5.47 mmol) of potassium tert-butoxide, and the mixture is left to stir at RT for 30 min. Then 624 mg (3.65 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added. The mixture is stirred at RT for 6 h, water is added and the mixture is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. Purification is effected by preparative HPLC. The resulting product fraction is purified further by chromatography on silica gel (eluent: dichloromethane, then 10:1 dichloromethane/methanol). This affords 158 mg (15% of theory) of the desired compound as a solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)o1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)o1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-furancarboxylate (0.70 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate as colorless crystals (0.41 g, yield 46%) from a fraction eluted with acetate-hexane (9:1, v/v). Recrystallization from ethyl ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CN1C=CN=C1.CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 52.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1 N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2c1nc(NC(=O)c1cc3ccccc3cn1)n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a solution of 0.031 g (0.18 mmol) of isoquinoline-3-carboxylic acid in DMF (1 mL) was added 0.085 g (0.22 mmol) of HBTU and 0.1 mL of DIEA. The mixture was stirred for 5 min, then added 0.04 g (0.18 mmol) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester in one portion. The reaction mixture was stirred for 1 h. After usual workup, 45 mg (73%) of 1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was isolated after purification by column chromatography eluting with DCM/methanol (v/v from 15:1 to 10:1). LCMS: 437 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 12.8 (s, 1H), 9.41 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.84 (t, 1H), 7.77 (m, 3H), 7.51 (d, 2H), 7.32 (m, 4H), 5.63 (s, 2H), 3.99 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:14][O:13][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([O:12][CH2:20][CH3:21])=[O:11]
Reactant: CO[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Temperature: 25 °C

Procedure:
A solution of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (35 g) in 140 ml of ethanol was mixed with 5.66 ml of concentrated sulfuric acid and stirred at room temperature until complete as indicated by HPLC. The ethanol was removed via vacuum distillation (55° C./28″Hg) and 110 ml of water was added. The pH was adjusted to about 7 to 8 with sodium bicarbonate, and the mixture was extracted with add 50 ml ethyl acetate (3×50 ml). The organic layers were combined, washed with 50 ml 20% NaCl solution, dried with 15 g of magnesium sulfate, and concentrate product to afford ethyl (2S)-2-methoxy-3-(4-hydorxyphenyl)propanoate as an oil. 1H-NMR (CDCl3): 7.1 (d, 2H); 6.7(d, 2H); 4.2(m, 2H); 3.9(m, 1H); 3.6(s, 3H); 2.95(m, 2H); 1.25(t, 3H). MS (ES): 223.2 (M−1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: C1CCNC1
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.51 cm3 of pyrrolidine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (95/5/1 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 440 mg of N-(6-chloro-1H-indazol-3-yl)-1-pyrrolidineacetamide in the form of an off-white powder melting at 168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH:13]1([CH3:25])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15]([C:22](Cl)=[O:23])[CH2:14]1.C(Cl)Cl.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:22]([CH:15]2[CH2:14][CH:13]([CH3:25])[CH2:18][CH2:17][CH:16]2[CH:19]([CH3:21])[CH3:20])=[O:23])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)C2CC(C)CCC2C(C)C)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
4-Methoxy-2-nitroaniline (5 g, 0.018 mol) was dissolved in pyridine (50) and treated with menthoyl chloride (3.57 g, 0.018 mol). The reaction mixture was heated to 50° C. and stirred vigorously for 6 h. The reaction mixture was cooled to room temperature and poured into a mixture of CH2Cl2 (100 mL) and 1N HCl (100 mL)). The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20 to 50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (4.9 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH2:16][CH:17]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=CCC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCCCC1
Yield: 96.1 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-cyclohexylacetaldehyde (Betapharma) (1.3 g, 10 mmol) in CH2Cl2 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).