Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2].CO.C(=O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C@@H:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2]
Reactant: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)ccc1C#N
Agent: O=C=O
Solvent: CO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OC[C@H]3[C@H]2C2CCCC2)ccc1C#N

Procedure:
The title compound was prepared from the 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid prepared in Example 61 using chiral resolution (e.g., Method G (Chiralcel OJ-H 30×250 mm; 60% methanol/carbon dioxide). Second eluting peak: tR=5.83 minutes (Chiralcel OJ-H 4.6×250 mm; 50% methanol/carbon dioxide).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])C(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:37][CH3:38])=[C:14]([CH:36]=1)[C:15]([NH:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([S:28](=[O:31])(=[O:30])[NH2:29])[CH:25]=2)[O:20][C:19]1([CH3:35])[CH3:34])=[O:16].[OH-].[Na+].C>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:37][CH3:38])=[C:14]([CH:36]=1)[C:15]([NH:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([S:28]([NH:29][C:3]([NH:2][CH3:1])=[O:8])(=[O:30])=[O:31])[CH:25]=2)[O:20][C:19]1([CH3:35])[CH3:34])=[O:16]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C

Procedure:
1.23 g (7.5 mmol) of N-methyltrichloroacetamide were added to 2.27 g (5 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 0.5 g (12.5 mmol) of finely powdered sodium hydroxide. After the mixture had been stirred at 80° C. for half an hour, it was introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol/DMF. The product had a melting point of 248° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:27][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=2)=[CH:29][CH:28]=1)#[N:16]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3ccncc3)cc2)n1)C(N)=O
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (80 mg, 0.334 mmol), 4-(pyridin-4-yl)aniline (56 mg, 0.329 mmol), K2CO3 (110 mg, 0.797 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 110 C for 4 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(4-(pyridin-4-yl)phenylamino)pyrazin-2-ylamino)butanamide (57 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[OH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]1[CH2:14][CH2:15][N:16]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:17][CH2:18]1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(C(O)c3ccccc3)CC2)nc1

Procedure:
Intermediate B-24 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-(hydroxyphenylmethyl)piperidine as starting materials. MS (M+1): 284.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc2sc(N)nc12
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccccc3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and benzoyl chloride in pyridine the title compound was obtained as a white solid (72% yield), MS: m/e=284.1 (M+).
Reaction SMILES: C[N:2](C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](=[O:22])[C@@H:14]([CH2:23][C:24]([OH:26])=O)[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=3[O:35][CH3:36])[C:11]=2[CH:37]=1.[Cl-].[NH4+].C(OP(C#N)(=O)OCC)C>C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:15](=[O:22])[C@@H:14]([CH2:23][C:24]([NH2:2])=[O:26])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=3[O:35][CH3:36])[C:11]=2[CH:37]=1
Reactant: CN(C)C=O
Reactant: COc1cccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COc1cccc([C@H]2O[C@H](CC(N)=O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c1OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A dimethylformamide solution of (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (2.0 g), ammonium chloride (1.2 g) and triethylamine (1.0 ml) was cooled in ice bath. To the solution were added diethylcyanophosphonate (0.85 g) and triethylamine (0.5 ml). The mixture was stirred for further 20 minutes, to which was added ice-water, followed by extraction with ethyl acetate. The organic layer was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from diethyl ether to give 1.0 g of (3R,5S)-7-chloro-5-(2, 3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide as colorless crystals, m.p. 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+]([O-])=O)=[C:5]([CH:14]=[CH:15][N+:16]([O-])=O)[N:4]=1>[Fe].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:15][NH:16][C:6]2=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc([N+](=O)[O-])c(C=C[N+](=O)[O-])nc1OC
Agent: [Fe]
Solvent: Cc1ccccc1
Product: COc1cc2[nH]ccc2nc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Heat a mixture of 2,3-dimethoxy-5-nitro-6-(2-nitrovinyl)pyridine, 8 (144 mg, 0.565 nmmol), Fe (0.6 g, 0.565 nmmol), SiO2 (0.565 g) under reflux in ACOH (3.4 mL) and toluene (5.7 mL). After 1 h, leave the reaction medium to cool to room temperature. Filter the reaction mixture and wash the solid with CH2Cl2 and discard. Then wash the filtrate with aqueous Na2SO3 at 1%/Na2S2O5, then with saturated NaHCO3, dry (MgSO4) and concentrate under vacuum. Purify the raw product by flash chromatography (EtOAc at 40%/heptane) to give 9 (46 mg, 46%) as a fawn-colored solid: 1H NMR (CDCl3) δ 8.04 (s broad, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 6.55 (m, 1H), 4.09 (s, 3H), 3.90 (s, 3H); Rf (EtOAc at 40%/heptane)=0.10; m/z obs.=178.94 (M+1).
Reaction SMILES: [N-]=C=O.[CH2:4]([C:6]1([CH2:21][CH2:22][N:23]=C=O)[C:18]2[N:17]([CH2:19][CH3:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:5].[OH-].[Na+]>Cl>[CH2:4]([C:6]1([CH2:21][CH2:22][NH2:23])[C:18]2[N:17]([CH2:19][CH3:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:5]
Reactant: CCn1c2c(c3ccccc31)CCCC2(CC)CCN=C=O
Agent: Cl
Agent: [N-]=C=O
Agent: [Na+]
Product: CCn1c2c(c3ccccc31)CCCC2(CC)CCN
Temperature: 100 °C

Procedure:
A suspension of the isocyanate, isocyanic acid 2-(1,9-diethyl-1,2,3,4-tetrahydrocarbazol-1-yl)ethyl ester (296 mg) described in Example 222, in 20% aqueous HCl (10 ml) is stirred and heated at 100° C. for 16 hr under nitrogen. The cooled solution is rendered alkaline witn 40% NaOH, saturated with NaCl and extracted with chloroform. The extract is dried (MgSO4) and concentrated to give the title compound, nmr (CDCl3) δ 0.7 (t, J = 7, 3H), 1.27 (t, J = 7, 3H), 4.0 (q, J = 7, 2H), 5.45 (b, 2H), 6.85-7.65 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:4].Cl.[F:33]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[Br:1][CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)([F:33])[CH2:14][CH2:13]1)=[O:11])=[O:4]
Reactant: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 235.2) but using compound 11.2 HCl salt instead of compound 1.5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Yield: 100 %

Procedure:
2-Chloro-N-(3-fluorophenyl)-4-(3-nitrophenyl)pyrimidin-5-amine (50 mg, 0.145 mmol) was added to the palladium/carbon (10 mg, 0.015 mmol) in ethanol (25 mL) and the applied hydrogen gas at 8 psi for 2 h at rt. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite; the solvent was removed by vacuum; and the crude material was purified by flash chromatography (2% CH3OH/DCM) to yield the title compound (35 mg, 0.145 mmol) as a solid. 1H NMR: (CDCl3, 400 MHz): δ 8.40 (s, 1H), 7.65 (m, 1H), 7.27-7.17 (m, 4H), 7.13-7.09 (m, 2H), 6.77 (m, 1H), 6.68 (m, 1H). ESI-MS: m/z 315.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([NH2:14])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CNCC=C1c1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@@H]1CNCC=C1c1ccc(F)cc1
Yield: 59.5 %

Procedure:
To an ethanol solution (1.0 mL) of (S)-2-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl]isoindoline-1,3-dione (170 mg, 0.402 mmol) synthesized in Reference Synthesis Example 210, hydrazine monohydrate (150 mg, 3.00 mmol) was added and the resultant mixture was stirred under reflux by heating for 2 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue and the resultant mixture was filtered again, followed by concentrating the resultant filtrate under reduced pressure to obtain the title compound (46.0 mg, yield 59%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH3:2].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:21]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]1[O:25][CH2:24]1
Reactant: ClCC1CO1
Reactant: CCCCC(CC)COCCCCCCCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCC(CC)COCCCCCCCCCCOCC1CO1
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A 200-ml flask equipped with a stirrer, reflux tube and dropping funnel was charged with 24.8 g (87 mmol) of 10-(2-ethylhexyloxy)decanol, 17.7 g (0.191 mol) of epichlorohydrin, 1.4 g (4.4 mmol) of tetrabutylammonium bromide and 25 ml of hexane. While stirring the mixture at 40° C., 29.2 g (0.35 mol) of a 48% aqueous solution of NaOH were added dropwise over 3 hours. After completion of the dropping, the stirring was continued further for 2 hours at 40° C. After the resultant reaction mixture was washed with water, and the solvent was distilled off under reduced pressure, the resultant residue was purified by column chromatography on silica gel, thereby obtaining 24.6 g (yield: 82.6%) of 10-(2-ethylhexyloxy)decyl glycidyl ether.
Reaction SMILES: [CH2:1]([C:4]1C(OC)=CC(C(Cl)=O)=CC=1OC)[CH:2]=C.[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[CH:21]=1.C(Br)C=C.COC(=O)C1C=C(OC)C=C(OCC=C)C=1.COC(=O)C1C=C(OC)C(CC=C)=C(O)C=1>>[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[CH2:4][CH:1]=[CH2:2]
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: C=CCc1c(OC)cc(C(=O)Cl)cc1OC
Agent: C=CCOc1cc(OC)cc(C(=O)OC)c1
Agent: C=CCc1c(O)cc(C(=O)OC)cc1OC
Solvent: C=CCBr
Product: C=CCc1c(O)cc(OC)cc1C(=O)OC

Procedure:
4-Allyl-3,5-dimethoxy-benzoyl chloride. Starting from 3-hydroxy-5-methoxybenzoic acid methyl ester by reaction with allyl bromide, 3-allyloxy-5-methoxybenzoic acid methyl ester is prepared. B.p. 128°-30°C/0.4 mmHg. This compound is subjected to the allylic rearrangement performed as described by Tarbell in Organic Reactions, Vol. II, New York, 1944 and a mixture of 4-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester and 2-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester is obtained. By hydrolysis under alkaline conditions and separation by fractioned crystallization the pure 4-allyl-3-hydroxy-5-methoxybenzoic acid is obtained. M.p. 202°-3°C (from methanol). The reaction with dimethylsulfate according to the procedure described by F. Benington et al. in Journal Org.Chem. 25, 2066, 1960 affords the corresponding 4-allyl-3,5-dimethoxy-benzoic acid. M.p. 188°-90°C (from light petroleum). This compound is allowed to react with thionyl chloride and 4-allyl-3,5-dimethoxy-benzoyl chloride is prepared. M.p. 56°-57°C (from light petroleum).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]1[CH2:24][N:25]([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:26])[CH3:27])=[C:9]([C:8](=[O:28])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:14]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Br)cc2C(=O)c2ccccc2Cl)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(Br)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-bromo-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-bromo-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol- 5-yl]methyl]-phthalimide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])=[C:4]([Cl:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[CH:40][C:39]=3[CH:43]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[C:6]([F:8])[C:5]([N:9]4[C:13]([CH2:14][C@@H:15]5[CH2:19][CH2:18][N:17]([C:20]([CH:22]6[CH2:24][CH2:23]6)=[O:21])[CH2:16]5)=[N:12][NH:11][C:10]4=[O:25])=[C:4]([Cl:26])[CH:3]=3)=[CH:43][C:39]=2[CH:40]=[CH:41]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2c(F)cc(Br)cc2Cl)C1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2c(F)cc(-c3ccc4occc4c3)cc2Cl)C1
Temperature: 100 °C

Procedure:
To a microwave vial were added 4-(4-bromo-2-chloro-6-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.027 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (0.04 mmol), cesium carbonate (0.08 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0012 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (0.3 mL) and water (0.15 mL). The mixture was heated for 15 h at 100° C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, and concentrated to afford the title product as an off-white solid and nearly equal mixture of atropisomeric diastereomers (7.0 mg, 54%). MS(ES)+ m/e 481.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:41]3([OH:44])[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=C1CCOCC1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (4.4 mL of a 1.7 M solution in pentane) was added over a period of five minutes, and the resulting dark-colored solution was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (901 mg, 9.0 mmol) was added, and reaction mixture was stirred for 10 minutes. The −78° C. bath was replaced with a 0° C. bath, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography (eluting with ethyl acetate) and heated in refluxing 1 M hydrogen chloride in ethanol (50 mL) for one hour. The solution was allowed to cool to room temperature and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified by automated flash chromatography and recrystallized from acetonitrile to provide 430 mg of 4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 209-211° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=2[CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>C1COCC1.CO.O>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[C:5]4([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]4)[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(=O)O)CC4)n3)cc2)CC1
Temperature: 40 °C
Reaction time: 84 h
Yield: 228.7 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A4) (0.304 g, 0.487 mmol) and LiOH.H2O (204 mg, 4.87 mmol) in THF (7 mL), MeOH (7 mL) and H2O (1.5 mL) was stirred at room temperature overnight. The resulting mixture was then heated to 40° C. and stirred for 3.5 days. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL). Aqueous HCl (2 M, 50 mL) was added cautiously and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL), and then the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo to give the title compound A5 as a yellow oil (680 mg, 98%); LCMS-A: rt 6.793 min; m/z 609 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[S:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21])([CH3:4])[CH3:3]>C(Cl)(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[CH:7][C:6]=1[S:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(S[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method described in Example 83, except that the title product of Example 90, Compound B, was substituted for the title product of Example 82, Compound B. The structure was supported by NMR, Ir, optical rotation (CHCl3, 25° C.; 589 nm -10.5°±2.69°; 365 nm -63.4°±18.1°), chiral HPLC (chiralpak-AD) major 98.84%, minor 0.68% (product of Example 90, Compound A) and elemental analysis.