Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:17])[CH2:10]2)#[N:6].NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([N:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]#[N:6])[CH:8]=3)[CH2:12]2)=[O:17])[CH2:28][CH2:27]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)NCCCCC1CCNCC1)C2
Solvent: CC(=O)Cl
Product: N#Cc1ccc2c(c1)CN(C(=O)NCCCCC1CCN(C(=O)c3ccccc3)CC1)C2

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and 5-cyano-N-(4-(piperidin-4-yl)butyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.83 (s, 1H), 7.75 (dd, J=7.9, 1.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.41-7.44 (m, 3H), 7.31-7.38 (m, 2H), 6.36 (t, J=5.5 Hz, 1H), 4.60-4.64 (m, 4H), 4.30-4.53 (m, 1H), 3.42-3.71 (m, 1H), 3.02-3.10 (m, 2H), 2.64-3.00 (m, 2H), 1.56-1.84 (m, 2H), 1.37-1.54 (m, 3H), 1.24-1.31 (m, 4H), 0.93-1.16 (m, 2H); MS (ESI(+)) m/e 431 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].[Cl-].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:22]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2′-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilIyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hr. and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][NH2:20]>>[CH:2]1[C:11]2[C:6](=[C:7]([S:12]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:21])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCCCCN
Agent: Cl
Product: NCCCCNS(=O)(=O)c1cccc2cnccc12
Yield: 61.9 %

Procedure:
According to the method of Reference Example 2, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (18.8 g) and 1,4-butylenediamine (25 g) to obtain the title compound (12.3 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1.[NH2:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH3:34])=[CH:28][C:29](=[O:33])[O:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O>[CH3:34][C:27]1[C:26]2[C:31](=[CH:32][C:23]([NH:22][C:19]([C:17]3[CH:16]=[CH:15][C:13]4[N:14]=[C:10]([C:4]5[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH3:9])[NH:11][C:12]=4[CH:18]=3)=[O:20])=[CH:24][CH:25]=2)[O:30][C:29](=[O:33])[CH:28]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)Cl)cc2[nH]1
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Nc3ccc4c(C)cc(=O)oc4c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carbonyl chloride HCl salt (from Example 1-247) (160 mg) and 7-amino-4-methyl-chromen-2-one (87 mg) was added DIPEA (0.27 mL). The resulting solution was stirred at room temperature for 18 h. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by an amino column using hexanes/ethyl acetate (1:4) and gave 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (4-methyl-2-oxo-2H-chromen-7-yl)-amide as a white solid; MS (ESI)m/z 424 (M+H).
Reaction SMILES: B(Br)(Br)[Br:2].[CH2:5]1[O:13][CH2:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2>C(Cl)Cl>[Br:2][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][OH:13]
Reactant: BrB(Br)Br
Reactant: c1ccc2c(c1)COC2
Solvent: ClCCl
Product: OCc1ccccc1CBr
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1M BBr3 in CH2Cl2 (49.2 mL, 49.2 mmol) cooled at 0° C. was added dropwise over 45 minutes a solution of phthalan (17.40 g, 142.6 mmol) in CH2Cl2 (30 mL). After the addition, the mixture was heated to reflux (oil bath) for 1 hour, then cooled to room temperature and quenched with water (50 mL). The mixture was washed with H2O (100 mL), 50% saturated NaHCO3 (100 mL), H2O (100 mL), brine, dried (MgSO4) and concentrated in vacuo to give a brownish solid, which was crystallized from EtOAc/hexane to afford 16.442 g of the title compound of this step as a light yellow crystalline compound. The mother liquor was concentrated and the residue crystallized (EtOAc/hexane) to yield an additional 6.30 g of the title compound of this step (total amount of product: 22.742 g, 80% yield).
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CCC(=O)O.NCCC(N)=O.[NH2:36][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40].N[C@H](C(N)=O)CC(=O)N>>[NH2:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40]
Reactant: NC(=O)C[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)C[C@H](N)C(N)=O
Agent: NCCC(N)=O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
CyanoAla, Thio-Asn, Asp, Gln, Glu, β-Ala-NH2, D-Asn, Asn-NH2
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[CH:14]=[CH:13][CH2:12]4)[CH2:9][C@@H:8]([OH:23])[C:7]=2[CH:6]=1)(=O)C.C([O-])(=O)C>>[CH3:16][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][C@@H:8]([OH:23])[C:7]4[CH:6]=[C:5]([OH:4])[CH:22]=[CH:21][C:20]=43)[C@@H:11]1[CH2:12][CH:13]=[CH:14]2
Reactant: CC(=O)Oc1ccc2c(c1)[C@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: CC(=O)[O-]
Product: C[C@@]12C=CC[C@H]1[C@@H]1C[C@@H](O)c3cc(O)ccc3[C@H]1CC2

Procedure:
6β-HYDROXYESTRA-1,3,5(10),16-TETRAEN-3-YL ACETATE (Acetate of E12/N1)
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[F:31].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:20])[CH2:19][CH2:18]2)=[O:27])=[CH:24][C:23]=1[F:31]
Reactant: O=C(NC1CCC1)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CCC4)c3)CC2)cc1F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of N-cyclobutyl-3-(piperazin-1-ylmethyl)benzamide (8.78 mmol, 2.4 g), 4-amino-3-fluorobenzoic acid (8.78 mmol, 1.362 g) and triethylamine (26.3 mmol, 3.67 mL, 2.67 g) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (13.17 mmol, 7.84 mL, 8.38 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour then was diluted with ethyl acetate/sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 55 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and [(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.66 g) as starting materials, N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained. melting point: 120-121° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCO)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g), 3-(4-hydroxyphenyl)propanol (2.50 g), potassium carbonate (3.40 g) and N,N-dimethylformamide (25 ml) was stirred for 14 hours at 60° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (4.46 g, yield 84%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 70-71° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1C)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
150 mg (0.470 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-methylbenzonitrile are dissolved under an argon atmosphere in 10 ml of abs. dichloromethane, and 178 mg (0.939 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 110 mg (67.4% of theory) of the title compound are obtained.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[C:12]([O:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH:2]=[C:3]([CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[N:21]=[C:20]1[NH2:22])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: CCOC(OCC)C(=O)CBr
Product: CCOC(OCC)c1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A mixture of 3-bromo-1,1-diethoxy-propan-2-one (21.3 g, 95 mmol) (Step 179.9) and N-tert-butoxycarbonylguanidine (45.3 g, 284 mmol, 3 equiv) (Step 179.10) was stirred at 50° C. for 8 h. The reaction mixture was concentrated, diluted in EtOAc/H2O and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (DCM/EtOAc, 3:7) followed by trituration in Et2O to afford 11.3 g of the title compound as a white solid: ES-MS: 286 [M+H]+; Rf=0.34 (DCM/EtOAc, 3:7).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[N:19]([CH2:33][C:34](=[O:39])[NH:35][CH:36]([CH3:38])[CH3:37])[C:18]3=[O:40])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[CH:36]([NH:35][C:34](=[O:39])[CH2:33][N:19]1[C:18](=[O:40])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[N:21]=[C:20]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH3:38])[CH3:37]
Reactant: COc1cccc(-c2nc3ccc(N4CCCN(C(=O)OC(C)(C)C)CC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[3-(Isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VII.1) (50 mg, 0.091 mmol) was treated with 4 N HCl/MeOH (10 mL) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 2a) (40 mg, 0.091 mmol, 100%) as the hydrochloride salt. Data for N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 2a) (EXAMPLE 2a) hydrochloride salt: MS (ESI) m/z: 450 ([M+H]+)
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][Si](C(C)(C)C)(C)C)=[C:6]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH2:9][O:8][C:7]2=[O:16])[CH:2]=[CH2:3].[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27]>C(O)(=O)C>[C:26]([O:17][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:12]([O:13][CH3:14])[C:11]([CH3:15])=[C:10]2[C:6]=1[C:7](=[O:16])[O:8][CH2:9]2)(=[O:27])[CH3:25]
Reactant: C=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)O
Product: C=CCc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of 5-allyl-4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran [(J. W. Patterson and G. Huang, Chemical Communications, 1579 (1991)](7.5 g) in acetic acid (95 ml) and acetic arthydride (95 ml) was refluxed for 18 hours, then cooled and poured into ice water. The solution was extracted with ethyl acetate, and the extract washed with dilute aqueous sodium bicarbonate, followed by water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give 4-acetoxy-5-allyl-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran, mp 101°-102° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:25]2([CH2:29][CH2:28][CH2:27][O:26]2)[CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:22][C:25]4([CH2:29][CH2:28][CH2:27][O:26]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1COC2(C1)CNC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(CCCO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octane hydrochloride (1359656-11-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:9]2[O:10][CH:22]=[C:20]([CH2:19][Cl:18])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=C(c1ccccc1)c1ccccc1
Product: ClCc1coc(C=C(c2ccccc2)c2ccccc2)n1
Yield: 49 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,3-diphenylpropenamide was allowed to react with 1,3-dichloroacetone to give 2-(2,2-diphenylethenyl)-4-chloromethyloxazole. The yield was 49%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 107-108° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]([OH:27])=O)[C:6]2[N:10]=[C:9]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:8][C:7]=2[CH:24]=1)#[N:2].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.S(O)(O)(=O)=O.[NH2:66][C:67]1[NH:68][CH:69]=[CH:70][N:71]=1>O.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:25](=[O:27])[NH:66][C:67]2[NH:68][CH:69]=[CH:70][N:71]=2)[C:6]2[N:10]=[C:9]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:8][C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1cc(C(=O)O)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
0.20 g (0.56 mmol) of 6-cyano-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid and 0.21 g (0.56 mmol) of HBTU were combined in a flask charged with 3 mL of DMF and 1 mL of DIEA. This reaction mixture was then treated with 0.07 g (0.56 mmol) of 2-amino-imidazole sulfate and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg of isoquinoline-3-carboxylic acid [6-cyano-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 424.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.Br[C:17]1[N:18]=[C:19]([CH2:36][CH3:37])[C:20]([NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@@H:27]2[OH:35])=[N:21][C:22]=1[CH2:23][CH3:24]>>[CH2:36]([C:19]1[C:20]([NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@@H:27]2[OH:35])=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[N:18]=1)[CH3:37]
Reactant: COc1cc2c(cc1B(O)O)CCCC2
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Yield: 67 %

Procedure:
Following the general procedure of Example 1 Step 3 and making non-critical variations but substituting 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid (Preparation 2) with 3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid (Preparation 1), and substituting 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine with (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]indan-2-ol (303 mg, 0.84 mmol) and gave 550 mg of a crude orange oil. The crude was purified on a Biotage MPLC column (90 g column, 18% ethyl acetate in heptane) to give 249 mg (67%) of (1R,2S)-1-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol as a glassy paste. Rf 0.20 (25% ethyl acetate in heptane). OAMS supporting ions at: ESI+444.3. HRMS (ESI) calcd for C28H33N3O2+H1 444.2651, found 444.2635.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:24]=[CH:23][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:13][C:9]=2[CH:8]=1)=[O:6].Cl>O.C1COCC1>[N+:20]([C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:9]3[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:24]=[CH:23][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1ccc2nc(-c3cccc([N+](=O)[O-])c3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2nc(-c3cccc([N+](=O)[O-])c3)oc2c1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
A solution of lithium hydroxide (1.78 g, 65.0 mmol) in water (10 ml) was added to a solution of 2-(3-nitrophenyl)benzoxazole-6-carboxylic acid methyl ester (4.0 g, 14.8 mmol) in THF (30 ml). The reaction was heated to 60° C. for 4 h. The cooled reaction mixture was acidified with 2M HCl and the precipitate filtered, washed with water and dried under vacuum to give the subtitle compound (3.47 g, 92%). The product was used directly in the next step without purification.