Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.NO.F[P-](F)(F)(F)(F)F.[N:34]1([O:43][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH:34][OH:43])=[O:14])=[CH:11][N:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1ccc(-n2cc(C(=O)O)c(-c3ccc(Br)cc3)n2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cc(C(=O)NO)c(-c3ccc(Br)cc3)n2)cc1
Yield: 3.2 %

Procedure:
A solution of 3-(4-bromophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid 65 (0.30 g, 0.804 mmol), hydroxylamine hydrochloride (0.112 g, 1.608 mmol), BOP (0.427 g, 0.965 mmol) and triethylamine (0.336 mLs, 2.412 mmol) in pyridine (10 mLs) was stirred at room temperature for 2 h. All solvents were then removed under reduced pressure, and the residue diluted with brine and aq. HCl until pH=1. Following extraction with EtOAc, the combined organic extracts were dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using 50-100% EtOAc/hexanes as the eluent to afford title compound 66 (10 mgs, 3% yield) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:14][CH:13]2[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])(=[O:11])=[O:10])[CH:6]=[C:5]([Cl:24])[C:3]=1[NH2:4].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([S:9]([NH:12][CH:13]([CH2:14][O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])(=[O:11])=[O:10])=[CH:6][C:5]=1[Cl:24]
Reactant: Oc1ccccc1
Reactant: CC1CCN(C(=O)C2CN2S(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Product: CC1CCN(C(=O)C(COc2ccccc2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Examples 100-105 are prepared from 2,6-dichloro-4-({2-[(4-methylpiperidin-1-yl)carbonyl]aziridin-1-yl}sulfonyl)aniline and the appropriate phenol in the same manner that Example 99 is synthesized.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+].O>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde (4.3 g) (Example I1) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1) to give 4-bromo-3-methyl-benzaldehyde oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 2.40 (s, 3H) ppm.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CO)cs2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-(4-hydroxymethyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (0.83 g, 2.8 mmol) and triethylamine (836 μL, 6.0 mmol) in dichloromethane (3 mL) was cooled to 0° C., and a solution of methanesulfonyl chloride (235 μL, 3.0 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was warmed to ambient temperature, stirred for 2 h, diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid and brine, and dried (MgSO4). The organic layers were concentrated under reduced pressure and purified by silica gel chromatography using 25-50% ethyl acetate in hexanes as eluant to give 0.20 g of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.CCN(CC)CC.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1.C(OC(=O)CCC)(=O)CCC>CN(C1C=CN=CC=1)C.O>[C:43]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[O:19])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:44])[CH2:42][CH2:41][CH3:45]
Reactant: C1CCOC1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CCCC(=O)OC(=O)CCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)NS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4[nH]3)c(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.92 g, 2 mmol), DMAP(0.024 g, 0.2 mmol) and Et3N (0.2 g, 2.1 mmol) in 100 ml o THF was added butyric anhydride (0.64 g, 4 mmol). The reaction mixture was stirred at room temperature overnight. The clear solution was then poured into 150 ml of H2O and extracted with CH2Cl2. The combined organic phase was washed with water, dried over MgSO4, and concentrated to dryness. Recrystallization from EtOAc/hexenes gave 0.80 g (75%) of the title compound as a red solid, mp 155–165° C. 1H-NMR (300 MHz, Acetone-d6) δ 10.55 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=8 Hz, 2H), 8.13–8.20 (m, 3H), 7.89 (d, J=16 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.02–7.07(m, 1H), 6.95–7.00 (m, 2H), 6.90 (s, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 2.29 (t, J=8 Hz, 2H), 1.48–1.56 (m, 2H), 0.81(t, J=8 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO)OC
Reaction time: 72 h

Procedure:
To a suspension of 3.33 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 20 ml of methanol is added 11.35 g of 2,2-dimethoxyethylamine at room temperature, and the mixture is stirred for 3 days. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound is obtained as colorless foam in a yield of 2.062 g.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:14](Cl)([CH3:17])([CH3:16])[CH3:15]>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1
Reactant: CC(C)(C)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.10 g (22.6 mmol) of aluminum chloride are added all at once to a mixture of 63.5 g (339 mmol) of p-bromoanisole and 31.4 g (330 mmol) of tert.butyl chloride. The mixture is stirred at ambient temperature until the evolution of gas ceases (about 15 minutes). The mixture is then heated at 80° C. for 15 minutes and poured into ice. 300 ml of water are added and the mixture is extracted with ether.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 110 mg, 0.36 mmol) in dichloromethane (4 ml), at 0° C. under nitrogen was added pyridine (56 μl, 0.72 mmol) then dropwise over 5 minutes ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol). The mixture was allowed to warm to room temperature and was stirred for 16 hours. Further pyridine (56 μl, 0.72 mmol) and ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol) were added and the mixture was stirred for 2 hours. The crude mixture was purified by silica (40 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (48 mg, 34%).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:38]([NH:37][C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C(=O)NC(C)(C)C)cc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccc(C(=O)NC(C)(C)C)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-(4-{2-[2-(4′-tert-butylcarbamoylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product as a solid. 1H NMR (400 MHz, d6-DMSO) δ8.12 (t, J=1.2 Hz, 1H), 7.90-7.73 (m, 6H), 7.56 (t, J=7.2 Hz, 1H), 6.82-6.74 (m, 4H), 4.17 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.34 (s, 3H), 1.36 (s, 6H); MS (EI) 557.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:37])/[C:13](=[N:27]\[O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:38])[N:8]2[S:39]([OH:42])(=[O:41])=[O:40])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:37])/[C:13](=[N:27]\[O:28][CH2:29][C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:38])[N:8]2[S:39]([OH:42])(=[O:40])=[O:41])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Yield: 31.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (97 mg, 0.154 mmol), DCM (1.54 mL) and TFA (711 μl, 9.23 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (22.7 mg, 22%) as a white powder. LCMS: Rt=0.28 min, m/z=475.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J=9.0 Hz, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 6.80 (s, 1H), 5.25 (dd, J=9.0, 5.9 Hz, 1H), 4.69-4.49 (m, 4H), 4.36 (dt, J=7.4, 4.9 Hz, 1H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:18]=[C:17]([NH:19][C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26]C(=O)OC(C)(C)C)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[CH:15]=3)[N:10]=2)=CC=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[NH:19][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[CH:15]=2)[N:10]=[C:9]([NH2:8])[N:18]=1
Reactant: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3N)c2c1
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To a solution of 9.37 g of tert-butyl (1R,2S)-2-({2-[(4-methoxybenzyl)amino]-6-methylquinazolin-4-yl}amino)cyclohexylcarbamate in 30 ml of methylene chloride, 95 ml of trifluoroacetic acid was added under ice cooling, and then the mixture was stirred for 72 hours. The reaction solution was concentrated, neutralized with a saturated sodium hydrogencarbonate solution, extracted with chloroform:methanol=10:1 and then dried. The solvent was distilled off and the residue was purified by Fuji Silysia NH silica gel column chromatography (chloroform:methanol=50:1) to obtain 4.60 g of the desirable compound.
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]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.3 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (460 mg, 1.12 mmol), potassium carbonate (201 mg, 1.46 mmol) and methyl iodide (207 mg, 1.46 mmol) in N,N-dimethylformamide (4.5 mL) was stirred at room temperature for 9 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (363 mg, 0.855 mmol, 76%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:13]=2[F:22])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:23]([Cu])#[N:24]>CN1C(=O)CCC1.C(Cl)Cl>[F:22][C:13]1[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:9]1[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2]([C:23]#[N:24])=[CH:11][CH:10]=1
Reactant: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1
Temperature: 160 °C
Reaction time: 6.5 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 94.3) (3.09 g, 8.5 mmol) and CuCN (918 mg, 10.2 mmol, 1.2 equiv) in NMP (30 mL) was stirred for 6.5 h at 160° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/(10% aqueous solution of ethylenediamine) (200 mL, v/v 1:1), filtered through celite and the filtrate extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 1.63 g of the title compound as a white solid: ESI-MS: 310.1 [M+H]+; tR=4.41 min (System 1).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[CH:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 1-benzyl-3-chloro-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 385 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:36])(=O)=O>O.CO>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:36])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(-c4ccccc4)cc3)n2C)n(CC)c1=O
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Compound 163 (1.50 g, 3.89 mmol) obtained in Reference Example 104 was suspended in a mixed solvent of 13 ml of water, 3.9 ml of a 2N aqueous solution of sodium hydroxide, and 7 ml of methanol. To the suspension was dropwise added 0.55 ml (5.83 mmol) of dimethyl sulfate, and the resultant mixture was stirred at 60° C.; for 4 hours. Water (10 ml) was added thereto, and the deposited crystals were collected by filtration and dried. The obtained crude crystals were purified by silica gel column chromatography, followed by recrystallization from ethyl acetate to give 480 mg (yield 28%) of Compound 164 as yellow columns.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.[S:22]1[C:26]2[CH:27]=[C:28]([C:31](Cl)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.O>C1COCC1>[S:22]1[C:26]2[CH:27]=[C:28]([C:31]([CH:18]3[C:17](=[O:20])[CH2:16][CH2:15][C:14]4([O:13][CH2:12][CH2:11][O:21]4)[CH2:19]3)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: O=C(Cl)c1ccc2ncsc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, lithium hexamethyldisilazide (2.4 mL, 2.4 mmol) was mixed with THF (5 mL). The reaction was cooled to −78° C. 1,4-cyclohexane-dione monoethylene acetal (374 mg, 2.4 mmol), dissolved in THF (2 mL) was slowly added via dropping funnel. The reaction was stirred for 20 min at −78° C. It was then cannulated to a flask, cooled at −78° C., containing benzothiazole-6-carbonyl chloride (498 mg, 2.52 mmol) dissolved in THF (5 mL). After the addition, the reaction was stirred at −78° C. for 1 hr, and then allowed to warm to room temperature. After 12 h, water (30 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (20 mL), water (20 mL), bicarb (20 mL), and brine (20 mL). It was then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (1:1 EtOAc/Hexanes) to yield 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 35%, light yellow solid).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.CS(OCCC1C=CC=CC=1)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:52]([N:51]([CH3:50])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Agent: CS(=O)(=O)OCCc1ccccc1
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1

Procedure:
This was synthesized by using 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate instead of 44643-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylbutylamine in place of piperidine as described in general procedure 2 to afford N-(4-(2-(butyl(methyl)amino)ethyl)phenyl)-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 1H NMR 400 MHz (CDCl3) δ 13.14 (s, 1H), 10.31 (br s, 1H), 8.42-8.36 (m, 1H), 8.0 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.62-7.5 (m, 2H), 7.39-7.27 (m, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.09-7.06 (m, 1H), 6.92-6.8 (m, 1H), 4.33 (t, J=6.3 Hz, 1H), 3.58-2.9 (m, 8H), 2.85 (s, 3H), 1.84-1.68 (m, 2H), 1.5-1.35 (m, 2H), 0.98 (t, J=7.4 Hz, 2H). LCMS m/e 531 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:37][CH:38]([C:48]1[O:49][C:50]([C:53]2[C:54](=[O:64])[N:55]([CH3:63])[C:56]3[C:61]([CH:62]=2)=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][N:52]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46]>CN(C=O)C.C(Cl)Cl>[CH3:63][N:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:62]=[C:53]([C:50]2[O:49][C:48]([C@@H:38]([NH:37][C:12]([CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]3)=[O:14])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46])=[N:52][CH:51]=2)[C:54]1=[O:64]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CCC(=O)CCCCCC(N)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C(=O)OC(C)(C)C)C1)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.3 eq), HOBt (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 10 min) was added to S)-3-(2-(1-amino-7-oxononyl)oxazol-5-yl)-1-methylquinolin-2(1 H)-one (1 eq), obtained as described above. The mixture was stirred o/n at room temperature. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated. The mixture was purified by flash chromatography on silica, eluting with EtOAc/petroleum ether (from 50% of EtOAc to 100% of EtOAc). MS (ES) C31H40N4O6 requires: 564.67, found: 565.