Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([F:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:20][C:14]1[CH:13]=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]=1[N+:17]([O-:19])=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
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: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Yield: 96.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 3.1 g of benzeneboronic acid, 5 g 5-bromo-2-fluoronitrobenzene and 22 mL 2 M sodium carbonate solution in 50 mL toluene and 50 mL ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a yellow oil. The oil was chromatographed on silica gel using 5% ethyl acetate in hexane to give 4.75 g (96% yield) of 4-fluoro-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:24])[CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])C)[CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.ClCC1[O:28][C:29]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][C:30]=2[N:31]=1>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:24])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:21][C:23]4[O:28][C:29]5[CH:35]=[CH:34][C:33]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[CH:32][C:30]=5[N:31]=4)[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCN(C(C)C)CC3)ccc2s1
Reactant: ClCc1nc2cc(-c3ccccc3)ccc2o1
Solvent: CN(C)C=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc5cc(-c6ccccc6)ccc5o4)CC3)ccc2s1
Temperature: 150 °C
Reaction time: 0 h

Procedure:
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ylpiperazinyl)propan-2-ol (0.035 g, 0.11 mmol) and DMF (1 mL) were placed in a Smith Process Vial™ (3 mL glass vessel) followed by the addition of 2-(chloromethyl)-5-phenyl-benzoxazole (0.027 g, 0.11 mmol). The vial was sealed and the mixture was heated in the Emrys Optimizer™ microwave at 150° C. for 300 sec, fixed hold time on, absorption level normal, pre-stirring 10 s. It was then cooled to room temperature, evaporated under reduced pressure and the residue was purified by flash chromatography (3% MeOH in CH2Cl2) to yield (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[(5-phenylbenzoxazol-2-yl)methyl]piperazinyl}propan-2-ol as a off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(4-Fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.103) (0.24 g, 0.68 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.21 g, 0.82 mmol) according to the general procedure VI. Obtained as a light brown solid (0.38 g), which was subsequently deprotected.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.BrC1C=C(C=CC=1)CBr.NC1C=CC=CC=1.C([Cl:70])(=O)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.[ClH:70]
Reactant: O=C(Cl)c1ccccc1
Agent: BrCc1cccc(Br)c1
Agent: CO[C@]12CC[C@@]3(C[C@@H]1COCc1cccc(NC(=O)c4ccccc4)c1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Solvent: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl

Procedure:
In a similar manner N-(3-((((4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-9-hydroxy-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)methoxy)methyl)phenyl)benzamide (Compound 74) was prepared from C using 3-bromobenzyl bromide, followed by conversion of the aryl bromide to the aniline, subsequent reaction of the aniline with benzoyl chloride and final cleavage of the p-methoxybenzyl group by TFA. Purification by flash column chromatography (silica gel, 0-10% MeOH/DCM) followed by HCl salt formation gave Compound 74 HCl salt as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.N.[C:7]1([O:17][CH3:18])[C:8](=[CH:10][CH:11]=[C:12]([CH:16]=1)[CH2:13][CH:14]=[CH2:15])[OH:9].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.C[O:35]S([O-])(=O)=O>CCCCCCCC.O>[CH2:15]([OH:35])/[CH:14]=[CH:13]/[C:12]1[CH:11]=[CH:10][C:8]([OH:9])=[C:7]([O:17][CH3:18])[CH:16]=1
Reactant: COS(=O)(=O)[O-]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCCCCCCC
Solvent: O
Product: COc1cc(/C=C/CO)ccc1O
Reaction time: 1.62 h

Procedure:
A dilute sulfuric acid solution or aqueous ammonia was dropwise added to the foregoing reaction solution for enzyme-activity determination from which the buffer is omitted (i.e., a solution comprising 50 μl of a 200 mM solution of eugenol in n-octane, 200 μl of a 50 mM aqueous solution of phenazine methosulfate and 675 μl of deionized water) to adjust the pH thereof from 5 to 7 and the resulting mixture is stirred at a temperature ranging from 25 to 55° C. for 15 to 180 minutes. After the completion of the reaction, the coniferyl alcohol is extracted from the reaction solution with an organic solvent such as ethyl acetate, chloroform, methylene chloride or ethyl ether, followed by purification thereof by a means such as silica gel chromatography, reverse phase liquid chromatography or vacuum distillation, optional discoloration with active carbon and vacuum drying to give colorless coniferyl alcohol powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:23])(=[O:19])[CH3:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A solution of 4-aminobenzonitrile (5 g, 42.3 mmol) and triethylamine (7.08 mL, 50.8 mmol) in dichloromethane (DCM) (40 mL) was cooled in an ice-water bath before the dropwise addition of 2-chloro-2-oxoethyl acetate (5.46 mL, 50.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM (50 mL) and the resulting solution washed with 2N HCl (50 mL). On mixing, precipitation occurred and the solid collected was filtered and dried under vacuum at 40° C. for 4 hours to yield a pale brown solid. The solid was dissolved in DCM (150 mL) and washed with 2N HCl (50 mL). The organic layer was collected via a hydrophobic frit and the solvent removed to yield the title compound as a cream solid (4.48 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].I[CH3:29]>C1COCC1.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
Methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate (6.7 g, 19.1 mmol) was dissolved in THF (20 ml) and stirred in an ice bath under nitrogen. Sodium hydride (1.17g of a 60% suspension in mineral oil, 29.5 mmol) was added and the mixture was stirred for 15 min in the cold, then for 15 min at ambient temperature. Iodomethane (2.4 ml, 5.47 g, 38.1 mmol) was added and the mixture was allowed to stir at ambient temperature under nitrogen for 72 hours. An additional 0.51 g of 60% sodium hydride suspension was added and the mixture stirred an additional 7 hours, then an additional 1.2 ml of iodomethane was added and the mixture stirred another 18 hours. An additional 0.53 g of sodium hydride suspension was added, the mixture was stirred 1.5 hours, then an additional 1 ml of iodomethane was added and the mixture stirred 6 hours. An additional 1 ml of iodomethane was added and the mixture stirred 18 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)-benzoate.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.[NH2:37][C:38](=[O:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C@H:25]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[C@@H:26]([NH:28][C:39]([C:38]([NH2:37])=[O:42])=[O:40])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:13][CH:14]=1
Reactant: NC(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
N,N-Diisopropylamine (0.049 mL, 0.30 mmol) was added to a suspension of (1R,2S)-1-(1-(4-fluorophenyl)indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (53 mg, 0.14 mmol), 2-amino-2-oxoacetic acid (12 mg, 0.14 mmol) and HBTU (62 mg, 0.16 mmoL) in dichloromethane (2 mL). The mixture was stirred at r.t. overnight. The clear solution was concentrated and purified by HPLC to give the title compound (43 mg, 69%).
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][O:32][C:33]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]([NH2:45])[CH2:38]2>ClCCl>[CH3:31][O:32][C:33]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]([NH:45][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:1])[CH2:38]2
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Reactant: COc1ccc2c(c1OC)CCC(N)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccc2c(c1OC)CCC(NC(=O)CCCCC(=O)NCCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (2.49 g) and carbonyldiimidazole (1.62 g) in dry dichloromethane (100 ml) was stirred under a nitrogen atmosphere for 2 hours at room temperature. A solution of 1,2,3,4-tetrahydro-5,6-dimethoxy-2- aminonaphthalene (2.07 g) in dichloromethane (20 ml) was added and the solution stirred at room temperature for 18 hours. The solution was washed with dilute hydrochloric acid, dilute sodium carbonate solution and water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to leave the sub-title compound which crystallised from isopropanol as colorless flakes (3.8 g), m.p. 191°-193°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:14][C@H:15]([O:17][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
To a solution of 2.8 g (7.8 mmol) (3R,5R)-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylic acid benzyl ester in 70 ml dry THF were consecutively added 1.0 g (8.5 mmol) benzoic acid, 1.7 g (8.5 mmol) diethyl azodicarboxylate and 2.2 g (8.5 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 2.8 g (78%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:21][Mg+].[Br-].O>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](=[O:5])[CH3:21]
Reactant: CON(C)C(=O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-methoxy-N-methyl-benzamide (1.8 g, 6.5 mmol, 1.0 eq) in THF (14 mL) at −20° C. was added MeMgBr (3.2 mL, 9.7 mmol, 1.5 eq). The mixture was stirred at 0° C. for 2 h then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 10:1) to give the title compound as a white solid (1.3 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A stirred mixture of 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.7 g, 4.2 mmol) and cyclopropane carbonyl chloride (0.46 mL, 5.1 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. To the mixture was added methanol (4 mL) at room temperature and the mixture stirred for 10 min. The solvent was removed in vacuo to give an oil. The oil was recrystallized from ethanol (20 mL) to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as a white solid (1.4 g, 71% yield); mp, 172-174° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.87; H, 6.13; N, 6.12.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:20][O:19][CH2:18]2)[CH2:13][CH2:12]1)([O-])=O.CCOC(C)=O>CO.[Ni]>[O:19]1[CH2:20][CH:17]([N:14]2[CH2:13][CH2:12][N:11]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH2:16][CH2:15]2)[CH2:18]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCN(C2COC2)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccncc1N1CCN(C2COC2)CC1
Yield: 99.9 %

Procedure:
1-(4-nitro-1-oxido-pyridin-1-ium-3-yl)-4-(oxetan-3-yl)piperazine (553 mg, 1.973 mmol) in MeOH (15 mL)/EtOAc (25 mL) was passed through the H-cube apparatus to hydrogenate over raney nickel at 20° C. and full H2 mode, flow rate 1 ml/min. The solvent was removed in vacuo to give the title compound 7l as an orange solid (462 mg, 100% Yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O>CN(C)C=O>[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(F)cc1OC(F)F
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C#N)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a solution of 1.7 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in 4.7 mL of dimethylformamide at 5° C. was added 250 mg of a 55% suspension of sodium hydride in mineral oil. The reaction volume was completed with dimethylformamide to about 8.5 mL. The reaction mixture was stirred for 30 minutes at 5° C. 4.3 mL of the resulting mixture was slowly added to a solution of 450 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 490 mg of 2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 97 %

Procedure:
5-amino-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide (850 mg) was suspended in 15 mL of ethanol and 4-hydroxybenzaldehyde (601 mg, 1.5 eq.) and piperidine (0.50 eq, 168 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.15 g, 97% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:35])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and tert-butyl(3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (Example C2) the title compound is obtained as pale yellow foam.