Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([CH:28]=1)[C:25](Cl)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:25](=[O:26])[C:24]1[CH:28]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)Cl)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 92 %

Procedure:
The reaction of 5-(octadecyloxy)-2-(3-phenylpropoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-(octadecyloxy)-2-(3-phenylpropoxy)benzoyl]glycine ethyl ester (92% yield, mp 54°-55°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[CH:15][CH:16]=3)[C:3]=12.[F:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:32][N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](Cl)=[O:40])[C:34]1=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH2:17][NH:18][C:39]([C:35]3[C:34](=[O:42])[N:33]([CH2:32][C:31]4[CH:43]=[CH:44][C:45]([F:46])=[C:29]([F:28])[CH:30]=4)[CH:38]=[CH:37][CH:36]=3)=[O:40])[C:3]=12
Reactant: NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Reactant: O=C(Cl)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Solvent: ClCCl
Product: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
43 mg of (3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanamine, 32 mg of crude 1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride were dissolved in DCM, TEA was added, then the resulted mixture was stirred at room temperature for overnight. The solvent was removed on a rotary evaporator and the crude was purified by chromatography to give 32 mg of N-(3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, yield: 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]([NH:32][CH2:33][CH2:34]O)[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:30][NH:32][CH2:33][CH3:34])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCNCCO
Product: CCNCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(ethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(ethylamino)ethanol following General Procedure K.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=CC(OC)=CC=1C=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:21][CH3:20])=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 88.6 %

Procedure:
According to the preparation of 42, 2,5-dimethoxybenzaldehyde (38) (1.2 g, 7.3 mmol) was used to afford 47 (1.8 g, 88.6%) as pale yellow prism crystals.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1
Reactant: OB(O)c1ccncc1Cl
Reactant: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccncc2Cl)c(-c2cccc(F)c2)n1
Temperature: 150 °C
Yield: 25.2 %

Procedure:
A microwave oven reactor was charged with 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 0.3 g, 1.11 mmol), (3-chloropyridin-4-yl)boronic acid (212 mg, 1.03 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1) (39 mg, 0.047 mmol), dioxane (8 mL) and a 1.2M aqueous solution of cesium carbonate was added (1.9 mL, 2.39 mmol). The mixture was heated to 150° C. for 10 min in the microwave oven, then cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane to dichloromethane/methanol 90:10) furnished the title compound as a yellowish solid (78 mg, 39%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:35])[CH:18]3[CH3:36])=[CH:15][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: Cl
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N4CCNCC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 4-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.076 g, 0.153 mmol) in HCl (4M in EtOAc, 30 mL) was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give 7-(2-fluoro-phenyl)-4-methyl-6-piperazin-1-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (0.065 g, 96%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.45-7.34 (m, 2H), 7.29-7.14 (m, 2H), 6.92 (s, 2H), 4.89 (q, J=6.8 Hz, 1H), 4.65-4.56 (d, J=13.2 Hz, 2H), 3.03 (m, 8H), 1.48 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1cccc2c1CCCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1cccc2c1CCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 14.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][C:11](C)=[O:12]>CS(C)=O.O1CCCC1>[C:4]1([C:1](=[O:3])[CH2:2][C:11](=[O:12])[CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)CC(=O)c1ccccc1

Procedure:
The procedure of Example 1 is repeated, using in place of acetophenone 17.4 g of acetone and increasing the amount of solvent from 100 g to 150 g of dimethyl sulfoxide/tetrahydrofuran.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[C:29]([F:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:31][C:27]1[CH:28]=[C:29]([F:30])[C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:32])[CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3c(F)cc(Cl)cc3F)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.30 g (4.57 mmol) of potassium cyanide was added to 1.05 g (2.28 mmol) of the compound from Example 111A in 21 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.74 g (83% of theory) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].B(Br)(Br)Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Cl)ccc2cc(O)ccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(2-Chloro-6-methoxy-naphthalen-1-yl)acetic acid ethyl ester (5.43 g, 19.48 mmol) and tetrabutylammonium iodide (9.35 g, 25.32 mmol) are dissolved under an atmosphere of argon in CH2Cl2 (110 ml). The reaction mixture is cooled to −78° C. and a 1 M solution of BBr3 in CH2Cl2 (48.7 ml, 48.7 mmol) is added during 15 minutes. After stirring at −78° C. for 10 minutes and at RT for 10 minutes, TLC analysis indicates complete consumption of starting material. The reaction mixture is poured on conc. aqueous NaHCO3 solution, and the mixture is vigorously stirred for 20 minutes at RT. After extraction with CH2Cl2, the organic layer is washed with brine and dried over Na2SO4. Purification by FCC (hexane/EtOAc 2:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.19 (t, J=9 Hz, 3H), 4.12 (q, J=9 Hz, 2H), 4.18 (s, 2H), 5.35-5.60 (br, 1H), 6.93 (s, 1H), 6.99 (d, J=10 Hz, 1H), 7.33 (d, J=10 Hz, 1H), 7.42 (d, J=10 Hz, 1H), 7.70 (d, J=10 Hz, 1H). ES+-MS: 265.2, 266.8 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reaction time: 72 h

Procedure:
847 mg (2.43 mmol) of ethyl 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml of ethanol, and 5 ml of 1 N sodium hydroxide was added thereto, and they were stirred for 3 days. The reaction solution was concentrated and treated in an ordinary manner with ethyl acetate as the extractant to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5](=[O:15])[C:4]1([F:17])[F:16].N12CCCN=C1CCCCC2>O1CCCC1>[F:17][C:4]1([F:16])[C:3](=[CH2:2])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:5]1=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC(CBr)C(F)(F)C1=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)-3,3-difluoro-2-oxopyrrolidine-1-carboxylate (50.1 g) in tetrahydrofuran (400 mL) was added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (25.0 mL) at 0° C. over 15 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1). The obtained crystals were washed with diisopropyl ether to give the title compound as colorless crystals (yield 28.1 g, 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=C(c1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a suspension of the ester 16 (94 mg, 0.27 mmol) in 75% aqueous methanol (2 mL) was added potassium hydroxide (0.045 g), and the reaction mixture was stirred at 50° C. for 14 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 2N aqueous hydrochloric acid, and then extracted with ether. The combined organic layers were washed with water and brine. The organic solution was then dried over anhydrous MgSO4, filtered and concentrated to afford a white solid. Recrystallization from benzene-hexane afforded the desired acid 48 as a white crystalline solid (0.074 g, 82%): m.p. 201°-204° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8](=O)[C:9]#[C:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.[NH2:30][NH2:31]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8]1[NH:31][N:30]=[C:10]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=1
Reactant: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)n[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an EtOH (10 mL) solution of the compound (395 mg) obtained in Example 14-(2), hydrazine hydrate (63 μL) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, water (50 mL) was added, and the organic layer extracted with AcOEt (50 mL) was dried (MgSO4), filtered and concentrated to give the titled compound (466 mg, pale brown amorphous.)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][CH2:6][O:7]C1CCCCO1.[Br-].[Mg+2].[Br-]>C(OCC)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][CH2:6][OH:7]
Reactant: FC(F)(F)COCCOC1CCCCO1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: OCCOCC(F)(F)F
Reaction time: 24 h

Procedure:
Combine 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluorethyl ether (2 mmol) and magnesium bromide (6 mmol) in diethyl ether (10 mL). After 24 hours, extract with water and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 2-hydroxyethyl 2,2,2-trifluorethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:16][CH2:17][C:18](O)=[O:19])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:16]1[CH2:17][C:18](=[O:19])[N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[S:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNCC(=O)O
Reactant: Cc1cccc(Cl)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N(c2c(C)cccc2Cl)C1=S
Yield: 36.6 %

Procedure:
The title compound was prepared by the procedure described in Example 11 using 6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of triethyl amine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (3.85 g) as a light pink solid, m.p. 97°-100° C. Anal. Calcd. for. C14H17Cl N2O S : C, 56.65; H, 5.77; N, 9.44. Found: C, 56.45; H, 5.67; N, 9.33. Mass spectrum (+FAB, [M+H]+) m/z 297.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34](OCC)=[O:35]>>[CH:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=CN1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][C:5]1([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].[CH:23]1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CO>[CH3:23][O:20][C:19](=[O:21])[CH2:18][O:17][C:5]1([CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)CCC1(OCC(=O)O)C(=O)CC(=O)c2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)COC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Yield: 90.4 %

Procedure:
A solution of Example 40B (20 mg, 0.066 mmol), 1,3-dicyclohexylcarbodiimide (20 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was stirred at 25° C. for 16 hours. The solution was and concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (19 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.47 (m, 1H), 0.68 (dd, J=13.24, 6.62 Hz, 6H), 0.76-0.91 (m, 1H), 1.15-1.34 (m, 1H), 1.81-1.98 (m, 1H), 2.05-2.22 (m, 1H), 3.40 (d, J=15.08 Hz, 1H), 3.57 (s, 3H), 3.76 (d, J=15.07 Hz, 1H), 5.75 (s, 1H), 7.43-7.57 (m, 1H), 7.55-7.70 (m, 2H), 7.89 (d, J=7.72 Hz, 1H), 11.94 (br. s, 1H); MS (ESI) m/z 319.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[S:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[N:24]=[CH:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:25]4[N:24]=[CH:23][S:22][CH:26]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cscn1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2cscn2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiazole-4-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and thiazole-4-carboxylic acid using method D. NMR; δH [2H6]—DMSO 10.35, (1H, s), 9.26,(1H, d), 8.62,(1H, t), 8.47,(1H, d), 7.92,(2H, d), 7.78-7.76,(2H, m), 7.44,(2H, d), 7.28,(1H, d), 3.16,(2H, t), 2.20,(3H, s), 1.04,(1H, m), 0.44,(2H, m), 0.24,(2H, m). LCMS: retention time 3.25 min, MH+392.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=O)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[K+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[N:19][OH:20])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Yield: 83.1 %

Procedure:
A mixture of 4-chloro 2',4'-dichlorobenzophenone (8 g.), hydroxylamine hydrochloride (2.9 g.), powdered potassium hydroxide (7.7 g.), ethanol (10 ml.) and water (2 ml.) was heated under reflux for 15 minutes. The mixture was poured into water (300 ml.) containing concentrated hydrochloric acid (30 ml.), and the precipitated oil was left to crystallise. The mixture was then filtered, and the solid residue (7.0 g., 83% yield) of 4-chloro-2',4'-dichlorobenzophenone oxime (m.p. 98°-100° C.) was used in the above process without further purification. A sample recrystallised from petrol also had m.p. 98°-100° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1>CO>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:1])=[O:19])[NH:15]2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Solvent: CO
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 25 °C
Yield: 86 %

Procedure:
A 2M solution of trimethylsilyldiazomethane in hexanes was added to a solution of 6-hydroxy-1H-indole-2-carboxylic acid (0.500 g, 2.82 mmol) in MeOH until the solution remained yellow in color. The solution was stirred at RT until the starting material was consumed as evident by TLC. The reaction mixture was partitioned between water and EtOAc then the organic layer was separated, dried over MgSO4, filtered and concentrated. Purification was accomplished by column chromatography (EtOAc/hexanes) to afford the title compound (0.464 g, 86% yield). 1H NMR (400 MHz, Acetone-d6): δ ppm 10.55 (br. s., 1H), 8.32 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.74 (dd, 1H), 3.85 (s, 3H). MS m/z=191.9 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:15][F:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=O)=[CH:12][C:4]1=2.[NH2:17][OH:18].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][CH2:2][C:3]1([CH2:15][F:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:17]/[OH:18])=[CH:12][C:4]1=2
Reactant: NO
Reactant: O=Cc1ccc2c(c1)C(CF)(CF)OB2O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (400 mg, 1.77 mmol) and NH2OH.HCl (148 mg, 2.12 mmol) in THF (25 mL) and H2O (5 mL) at rt was added NaOAc (203 mg, 2.48 mmol). The mixture was stirred at rt overnight, diluted with H2O and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (440 mg) was used directly in the next step without purification.