Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC(C)C)ccc1C(=O)O
Reaction time: 2 h

Procedure:
A 3.20 g portion of methyl 4-isopropoxy-2-methoxybenzoate was dissolved in 20 ml of tetrahydrofuran, and 30 ml of 2N sodium hydroxide aqueous solution was added, followed by 2 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure to give 2.60 g of 4-isopropoxy-2-methoxybenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([NH2:34])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24].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>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:19])[NH:34][C:31]3[NH:30][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[C:33]=4[N:32]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
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)c1cccc2[nH]c(NC(=O)c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Yield: 9 %

Procedure:
6-(4-Methoxycarbonyl-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (114 mg, 90%) was synthesized according to General Procedure A using 798 mg (2.82 mmol) of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester, 540 mg (2.82 mmol) of intermediate A (2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester), 1.28 g (3.38 mmol) of HBTU, 0.992 mL (5.64 mmol) of DIEA and 15 mL of DMF stirring at room temperature overnight. LCMS: 451 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41]S(C)(=O)=O)[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.1 %

Procedure:
A mixture of 1.100 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.939 g of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.56 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a dark oil which was purified by high pressure liquid chromatography using 40% ethyl acetatehexane to give 2.413 g (69% yield) of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH:30]1([C:33]2[CH:37]=[CH:36][NH:35][N:34]=2)[CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([C:33]2[CH:37]=[CH:36][N:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[CH2:14][N:13]5[CH:21]=[CH:22][CH:23]=[C:12]5[CH2:11]4)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=3)[N:34]=2)[CH2:32][CH2:31]1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: c1cc(C2CC2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2ccc(C3CC3)n2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 69.5 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.42 g), 60% sodium hydride in oil (0.20 g), 3-cyclopropylpyrazole (0.43 g) and dimethylformamide (50 ml), the product (1.22 g) was obtained as a crystalline solid, m.p. 163-164° C.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>N1CCCCC1>[CH2:1]([S:5][CH2:9][CH2:8][CH:6]=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC=O
Reactant: CCCCS
Solvent: C1CCNCC1
Product: CCCCSCCC=O
Temperature: 0.5 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
A mixture of butylmercaptan (180 g) and piperidine (1 drop) was cooled to 0.5° C in a flask equipped with a stirrer, dropping funnel, thermometer pocket and vent pipe and acrolein (112 g) was added dropwise over a period of 2-3 hours at such a rate as to maintain the temperature at less than 15° C. After all the acrolein had been added, the mixture was stirred for a further 20-24 hours, and the resulting mixture was taken as product (100% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:40]=[N:39][N:38]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1-c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cnn(Cc4cccc(Cl)c4)c3)c(C(=O)O)n1)CC2
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 9B (0.178 g), 1-(bromomethyl)-3-chlorobenzene (0.080 g) and cesium carbonate (0.170 g) was stirred together in N,N-dimethylformamide (2 mL) at room temperature. After 3 hours, the reaction was diluted with ethyl acetate (25 mL) and washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL) and stirred overnight. The mixture was concentrated, dissolved in dichloromethane and loaded onto silica gel and eluted using a gradient of 0.5% to 4% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.84 (s, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.60 (dd, 2H), 7.53-7.28 (m, 7H), 7.22-7.16 (m, 1H), 6.95 (d, 1H), 5.35 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([NH2:36])[CH3:35].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH2:34]([NH:36][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21])[CH3:35]
Reactant: CCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 55 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.465 g, 0.951 mmol) by treatment with commercially available ethylamine (2 M in THF, 2.38 ml, 4.76 mmol) and triethylamine (1.33 ml, 9.51 mmol) in THF (5 ml) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.260 g, 55%) as an off-white solid. MS (ISP) 498.3 [(M+H)+]; mp 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=1.CC(OC(C)=O)=O.C([O-])(=O)C.[K+].[N:29](OC(C)(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:12][N:29]=[CH:13]2
Reactant: Cc1cc(Oc2cccc(Cl)c2)ccc1N
Reactant: CC(C)(C)ON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
4-(3-Chloro-phenoxy)-2-methyl-phenylamine (0.87 g, 3.74 mmol) was dissolved in chloroform. Ac2O (0.878 g, 8.61 mmol) was then added dropwise over 10 min at 0° C. and the mixture was stirred for 1 h at 25° C. Potassium acetate (110 mg, 1.12 mmol) and t-butyl nitrite (829 mg, 8.05 mmol) were added to the reaction mixture and the mixture was heated at 80° C. for 16 h. This mixture was then concentrated, conc. HBr was added and the mixture was stirred for 16 h at 25° C. The pH of the mixture was adjusted to pH 7 using KOH solution and the resulting mixture was extracted with EtOAc (3×50 mL). The organic phase was washed with brine (3×10 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (11% EtOAc in hexanes) to afford 5-(3-chloro-phenoxy)-1H-indazole (152 mg, 17%). MS (M+H)+=245; 1H NMR (CDCl3) δ: 8.03 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (br.s., 1H), 7.21 (d, J=6.18 Hz, 1H), 7.16 (dd, J=6.5, 1.1 Hz, 1H); 7.08 (d, J=5.8 Hz, 1H), 6.93 (br.s., 1H), 6.86 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:29])[O:28][CH2:27]1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]([OH:28])([CH3:29])[CH3:27])[CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)CO1
Reactant: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1
Product: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)c(F)c2)C2CC2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-3-fluoro-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=402 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6](CC2C=CC(OC)=CC=2)[N:5]=[C:4]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.Br[C:29]1C(C2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)[N:30]=1>CN(C)C=O.O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:21][C:18]1[S:17][C:16]([C:4]2[C:3]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:2]([C:29]#[N:30])[NH:6][N:5]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1[nH]nc(-c2ccc(Cl)s2)c1-c1ccncc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
To 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 1 eq, 0.435 mmol) in 1 mL of N,N-dimethylformamide, were added zinc cyanide (0.65 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.09 mmol). The mixture was stirred for 5 mins at 160° C. in the microwave. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate was added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was dissolved in 1 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 20:1 to 10:1) to afford 19 mg of 3-(5-chloro-2-thienyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carbonitrile (15% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.C(Cl)(Cl)Cl>CN(C)C=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7]
Reactant: O=C1CCCCN1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CCCCN1CCCCBr
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
2-piperidone (1.98 g, 20.0 mmoles) was dissolved in 40 ml of dimethylformamide, 60% sodium hydride (840 mg, 21.0 mmoles) was added to the solution, and the mixture was stirred at 80° C. for 1 hour. After cooling the mixture to room temperature, 1,4-dibromobutane (21.6 g, 100 mmoles) was added, and the resulting mixture was stirred at room temperature for 12 hours. After chloroform was added to the reaction mixture, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water, and the solvent was evaporated. The residue was purified by chromatography on a silica gel column to give 1.30 g (yield 28%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH:18]=[C:14]([CH2:13][OH:12])[N:15]=[CH:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OCc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(CO)c2)c(F)c1
Yield: 75.4 %

Procedure:
3,4-Difluoronitrobenzene (23.85 g) was dissolved in acetonitrile (180 ml), followed by 4-hydroxymethylimidazole (14.7 g) and ethyldiisopropylamine (65.2 ml). The mixture was stirred and heated to reflux for 2 days. After cooling, acetonitrile was evaporated and the residue was shaken with a mixture of methyl t-butyl ether (200 ml) and water (100 ml), and the solid filtered. After washing with a mixture of methyl t-butyl ether (50 ml) and water (25 ml), the solid was dried in vacuo at 60° C. overnight, to give product (26.8 g) mp 157-159° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:17]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:18]1[CH2:19]2.Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH:7]1([C:1]2[CH:2]=[CH:3][C:4]([C:23]([C@H:17]3[CH2:19][C@H:18]3[C:20]([OH:22])=[O:21])=[O:24])=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1OC(=O)C2CC12
Reactant: c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc(C2CCCCC2)cc1)[C@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
14.3 g (89.2 millimoles) of cyclohexylbenzene are added dropwise to 23.7 g (0.18 mole) of anhydrous aluminum chloride in 50 ml of nitrobenzene at 10°-15° C., whilst stirring. 10.0 g (89.2 millimoles) of 1,2-cyclopropanedicarboxylic acid anhydride are then added, a little at a time, at the same temperature and thereafter the mixture is stirred for 20 hours at room temperature, followed by 1 hour at 50° C. The solution is introduced into a mixture of 500 g of ice and 50 ml of concentrated hydrochloric acid. The nitrobenzene is removed by steam distillation and the solid which has precipitated is filtered off at 10° C. and dissolved in aqueous sodium carbonate solution. The solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid which precipitates is filtered off, washed with water and dried under reduced pressure at 50° C. 19.9 g (82% of theory) of cis-2-(p-cyclohexylbenzoyl)-cyclopropanecarboxylic acid are obtained as almost colorless crystals of melting point 162°-163° C. after recrystallization from methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:78])[CH2:7][CH2:8][C@H:9]([C:40](=[O:77])[NH:41][C@@H:42]([C:64](=[O:76])[NH:65][C:66]1([CH:69]([OH:75])[CH2:70][C:71]([O:73]C)=[O:72])[CH2:68][CH2:67]1)[CH2:43][S:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH:10][C:11](=[O:39])[CH2:12][C@H:13]([OH:38])/[CH:14]=[CH:15]/[CH2:16][CH2:17][S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6](=[O:78])[CH2:7][CH2:8][C@H:9]([C:40](=[O:77])[NH:41][C@@H:42]([C:64](=[O:76])[NH:65][C:66]1([CH:69]([OH:75])[CH2:70][C:71]([OH:73])=[O:72])[CH2:67][CH2:68]1)[CH2:43][S:44][C:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[NH:10][C:11](=[O:39])[CH2:12][C@H:13]([OH:38])/[CH:14]=[CH:15]/[CH2:16][CH2:17][S:18][C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC1(C(O)CC(=O)O)CC1
Reaction time: 3.25 h
Yield: 86.2 %

Procedure:
To 7 (927.1 mg, 0.850 mmol) in THF (12 mL) at 0° C. was added LiOH (30.6 mg, 1.28 mmol) in water (3 mL) and the reaction mixture was stirred for 3.25 h. The mixture was then quenched with 1M HCl (aq) (20 mL), diluted with water (20 mL), and treated with EtOAc (60 mL). The layers were separated, and the product was extracted with EtOAc (3×60 mL). The organic layers were combined, washed with saturated brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the product 8 (789.1 mg, 86%) as a white solid (diastereoisomers 1:1 ratio). Compound 8 was used in the next step further purification [MS (ES+) 1097.4 (100%, [M+Na]+)].
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([I:26])[C:11]=12)[NH2:24]
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccnc3[nH]nc(I)c23)c(F)c1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Dissolved 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (50 mg, 0.102 mmol; prepared as in Example 7, Step B) in excess TFA (1 mL). The dark solution was stirred at 50° C. for (20 hours. The mixture was concentrated in vacuo, using toluene (2×5 mL) to azeotrope residual TFA. The crude was partitioned between CH2Cl2 and NaHCO3. The cloudy organic layer was evaporated and the resulting semi-solid triturated with diethyl ether to afford the desired product. Yield: 33 mg, 87%. LRMS (APCI pos) m/e 371.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])=[N:3]1.[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])=[N:3]1
Reactant: Cn1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 4-{1-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (944 mg, compound B70) in 1,4-dioxane (25 ml) is added a solution of hydrogen chloride in 1,4-dioxane (5.0 ml, 6.8 M). The reaction mixture is stirred for 17 h at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=O)([O-])=O.[CH3:13][NH:14][CH3:15].Cl[Sn]Cl.C1COCC1>CCOC(C)=O>[CH3:13][N:14]([CH2:7][C:6]1[CH:5]=[C:4]([CH:12]=[CH:11][CH:10]=1)[NH2:1])[CH3:15]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CNC
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-[(dimethylamino)methyl]aniline to generate the title compound. The 3-[(dimethylamino)methyl]aniline was prepared by treatment of commercial 3-nitrobenzoyl chloride with dimethylamine followed by sequential reduction with SnCl2 in EtOAc at 20° C. for 18 hours and then BH3 /THF.