Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([C:26](OC)=[O:27])[CH:22]=[CH:21]2.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([CH2:26][OH:27])[CH:22]=[CH:21]2
Reactant: COCCOc1cccc2ccc(C(=O)OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCOc1cccc2ccc(CO)cc12
Reaction time: 3 h

Procedure:
1.64 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at 0° C. to a solution of 0.26 g of methyl 8-(2-methoxyethoxy)naphthalene-2-carboxylate (residue 35) in 20 ml of dichloromethane. After 3 hours, the reaction solution is admixed with 2 ml of ethyl acetate, stirred for 1 hour, then admixed with 3 ml of I M sodium potassium tartrate solution and subsequently stirred further for 1 hour. The reaction mixture is concentrated by evaporation—the residue is admixed with water and extracted with ethyl acetate (3×). The combined organic phases are washed successively with 1M HCl and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14].BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCC(CN)NC(=O)OCc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CCC(CNc1nc(Cl)ncc1Br)NC(=O)OCc1ccccc1

Procedure:
benzyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate is synthesized by treating 5-Bromo-2,4-dichloropyrimidine with benzyl N-[1-(aminomethyl)propyl]carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) (M+H) 413
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[CH:17]1([C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1N=CN(C)C
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)C5CCCC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopentanecarbonyl-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 436.58 (C24H28N4O2S) was obtained in this way; MS (ESI): 437 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH:35](I)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH:35]([CH3:37])[CH3:36])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 6.3 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (544 mg), potassium carbonate (202 mg) and isopropyl iodide (356 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from acetone-hexane to provide the title compound as colorless solid (38 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:11]2=[O:13]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A suspension of 4-hydroxyphthalic acid (3.00 g) and 4-aminophenol (1.98 g) in glacial acetic acid (15 mL) was heated under nitrogen at 120° C. for 1.5 h. The brown reaction solution was cooled to room temperature, poured into water (200 mL) and allowed to sit undisturbed for 30 min. The precipitate was collected by filtration and washed with water (2×60 mL). The solid was dried under high vacuum at 50° C. for 18 h yielding the title compound (3.14 g) as a tan solid. 1H NMR (DMSO-d6): 10.99 (s, 1H), 9.72 (s, 1H), 7.76 (d, 1H, J=7.8 Hz), 7.18 (m, 4M), 6.86 (m, 2H); MS: 256 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:21]1[N:26]=[C:25]([CH2:27][O:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C:30]([CH3:33])([CH3:31])[CH2:29][O:28][CH2:27][C:25]1[N:26]=[C:21]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(O)COCc1cccc(Br)n1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)COCc1cccc(Nc2sc(-c3ccc(S(C)(=O)=O)cc3)cc2C(N)=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-5-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (150 mg, 0.51 mmol), 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (Example 217 Step 1) (125 mg, 0.48 mmol), Pd2 dba3 (46.3 mg, 0.051 mmol), K2CO3 (77 mg, 0.557 mmol) and X-Phos (120 mg, 0.25 mmol) were added to a 5 mL microwave vial. Degassed tert-amyl alcohol (1.2 mL) was added and the vial evacuated and back-filled with N2 (3×). The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with methanol, silica gel was added, and the solvent was removed in vacuo. Purification of the residue by flash chromatography (silica, 0-10% MeOH-DCM) gave the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:35])[F:34])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:34])[F:35])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 767.6 %

Procedure:
A solution of tert-butyl ((3S)-1-{4-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}pyrrolidin-3-yl)carbamate (0.05 g, 0.085 mmol) in 1 mL CH2Cl2 was treated with 0.1 mL of trifluoroacetic acid and stirred at ambient temperature overnight. Then the reaction mixture was partitioned with extra CH2Cl2 and saturated NaHCO3. The organic phase was isolated and dried (Na2SO4). The sovent was evaporated and the residue treated with excess HCl in diethyl ether. The solids were collected and dried to give 0.32 g of the title compound as the HCl salt.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C.O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a suspension of NaH (50.5 mg, 2.00 mmol) in DMF (1.00 mL) was added 1-(3-hydroxyphenyl)ethanone (136 mg, 1.00 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. To this mixture was added a solution of 1-bromo-3-chloropropane (188 mg , 1.20 mmol) in DMF (0.500 mL). The reaction mixture was stirred at room temperature for 5 h. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (4:1) to afford the desired product 1-[3-(3-chloropropoxy)phenyl]ethanone (235 mg, 55.2%): 1H NMR (400 MHz, CDCl3) δ 7.7 (d, 1H, J=6.6 Hz), 7.52 (s, 1H), 7.25 (t, 1H, J=6.6 Hz), 7.01 (m, 1H), 4.11 (t, 2H, J=7.9 Hz), 3.69 (t, 2H, J=7.9 Hz), 2.61 (s, 3H), 1.95-1.92 (m, 2H).
Reaction SMILES: [C:1]([O:12][CH:13]1[CH2:17][CH2:16][C:15]2([CH2:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:19](=[O:29])[CH2:18]2)[CH2:14]1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:30]1[CH:31]=[CH:32][C:33]2[S:38][N:37]=[C:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:34]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].CO.C(Cl)Cl>CC#N>[C:1]([O:12][CH:13]1[CH2:17][CH2:16][C:15]2([CH2:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27][N:42]3[CH2:43][CH2:44][N:39]([C:36]4[C:34]5[CH:35]=[CH:30][CH:31]=[CH:32][C:33]=5[S:38][N:37]=4)[CH2:40][CH2:41]3)[C:19](=[O:29])[CH2:18]2)[CH2:14]1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCCCCCCCCC(=O)OC1CCC2(CC(=O)N(CCCCBr)C(=O)C2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC1CCC2(CC(=O)N(CCCCN3CCN(c4nsc5ccccc45)CC3)C(=O)C2)C1
Yield: 51.6 %

Procedure:
8-(4-Bromobutyl)-7,9-dioxo-8-azaspiro[4.5]decan-2-yl decanoate (3.03 g, 1.00 equiv), BITP 14 (2.38 g, 1.69 equiv) and K2CO3 (3.37 g, 3.80 equiv) were reacted in 125 mL of CH3CN according to the general procedure. Flash chromatography with a 3% to 5% MeOH/CH2Cl2 gradient yielded 12 (2.02 g, 52%) as a yellow oil. Conversion to the oxalate salt and recrystallization from CH3CN/EtOH afforded the analytically pure test compound, m.p. 117-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.ICI.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-6-[1-(ethenyloxy)propyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (170 mg, 0.39 mmol) in dichloromethane (4.0 mL) was added a solution of diethyl zinc id hexane (1.0 M, 2.0 mL, 2.0 mmol) and diiodomethane (0.31 mL, 3.84 mmol) at 0° C. After stirring at 0° C. for 1.5 hr, aqueous ammonium chloride was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (87.7 mg, 0.196 mmol, 50%) as a pale yellow solid.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH:9]1[OH:18])(C)(C)C.C(O)(C(F)(F)F)=O.O=C1CCC(=O)N1OC([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)=O>C(Cl)Cl>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([OH:18])[CH:8]2[NH:7][C:6]([C:46]2[CH:47]=[CH:48][C:43]([C:40]3[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=3)=[CH:44][CH:45]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1c2cc(N)ccc2CC1O
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)C(NC(=O)c1ccc(-c3ccccc3)cc1)C(O)C2
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Combine (6-amino-2-hydroxyindan-1-yl)carbamic acid tert-butyl ester (1.5 g, 5.68 mmol) with 5 mL of TFA at 0° C. Stir the mixture for 1 h and then evaporate to dryness. Added 3.0 mL of triethylamine and 30 mL of methylene chloride the residue. To this mixture, add a solution of biphenyl-4-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.76 g, 5.96 mmol) in 15 mL of methylene chloride. Stir the resulting mixture for 12 h. Evaporate solvent and purify the residue by a column chromatography (silica gel/MeOH:CH2Cl2=9:1) to give 1.88 g (96% yield) of biphenyl-4-carboxylic acid (6-amino-2-hydroxyindan-1-yl)amide; MS 345 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25](Cl)(=O)C(Cl)=O.CO.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH3:25])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 83.1 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After the reaction was completed, a solution of 2 mL (1.58 g, 49.4 mmol) of methanol (MeOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.62 g (83% yield) of the title compound (24a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.07 (s, 3H), 2.25-2.32 (m, 2H), 3.22-3.26 (m, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.87 (s, 1H), 3.98 (d, J=9.2 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H), 4.63 (d, J=11.2 Hz, 1H), 7.32-7.36 (m, 5H) ppm. MS (ESI) m/z 392.90 (M+H)+, 414.91 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:14]=[C:15]2[CH2:19][CH2:18][CH2:17][C:16]=12)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:13]2[C:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:4]([OH:27])=[O:3])=[C:16]3[CH2:17][CH2:18][CH2:19][C:15]3=[N:14]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Yield: 61.2 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid ethyl ester (1 g, 2.6 mmol; example 1.3) in MeOH (56 ml) and 4 N aqueous NaOH (9.7 ml, 39 mmol) was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure, ice water/TBME 1/1 was added and the layers were separated. The aqueous layer was extracted one more time with TBME. The aqueous layer was acidified with 1 N aqueous HCl solution and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (570 mg, 1.59 mmol; 61%) as yellow oil which was sufficiently pure to be used in the next step. MS: m/e=359.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)[CH:35]=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH3:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: Cc1cc(C=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 69.28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60° C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95% yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.[CH2:15](I)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
5-Hydroxy-3,8-dimethylcarbostyril (4 g, 21.16 mmol) and allyl iodide (3.73 g, 22.2 mmol) were dissolved in dimethylformamide (44 ml), to which potassium carbonate (6.1 g, 44.2 mmol) was added, and stirred for 2 hours in a bath at 70° C. The solvent was distilled off, and the residue was dissolved in chloroform, and washed with water. After drying and condensing, the resultant residue was purified by silica gel chromatography (chloroform), and was subjected to recrystallization (chloroform-n-hexane) to obtain 4.32 g of the title compound as pale yellow prisms (89.2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[Cl:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>C(#N)C>[Cl:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([I:7])=[N:9]1
Reactant: Ic1n[nH]c2ccccc12
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCOCCn1nc(I)c2ccccc21
Yield: 55.7 %

Procedure:
Potassium carbonate (1.1 g, 8.2 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) and bis(2-chloroethyl)ether (1.5 g, 10.3 mmol) in ACN (20 mL) at rt. The reaction was heated to reflux overnight, and the filtered and concentrated. The residue was purified by silica gel chromatography to give 800 mg (56%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.47 (2H, t, J=5.6 Hz), 3.60 (2H, t, J=5.6 Hz), 3.94 (2H, t, J=5.2 Hz), 4.58 (2H, t, J=5.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.41-7.49 (3H, m). The minor isomer was not isolated or characterized.