Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=2)[C:3]=1[CH2:16][C:17]([OH:19])=O.[NH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=2)[C:3]=1[CH2:16][C:17]([NH2:20])=[O:19]
Reactant: CN(C)Cc1ccc2c(CC(=O)O)c(Cl)ccc2c1
Reactant: N
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2c(CC(N)=O)c(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Chloro-6-dimethylaminomethyl-naphthalen-1-yl)-acetic acid (276 mg, 0.99 mmol) is dissolved under an atmosphere of argon in DMF (3 ml). 1,1-Carbonyl diimidazole (177 mg, 1.09 mmol) is added, and the clear solution is stirred at RT for 3 h. A conc. aqueous solution of ammonia (25%, 6 ml) is added, and stirring is continued for 10 minutes at RT. TLC analysis indicates complete consumption of starting material. The reaction mixture is poured on water. The aqueous layer is extracted with EtOAc, which is then washed with brine and dried over Na2SO4. After removal of solvent, the residue is found to be pure title compound, with no need of purification. 1H NMR (d6-DMSO, 400 MHz): δ 2.18 (s, 6H), 3.53 (s, 2H), 4.08 (s, 2H), 6.96-7.08 (br, 2H), 7.48-7.68 (m, 2H), 7.78-7.86 (m, 2H), 7.96-8.00 (d, J=10 Hz, 1H). ES+-MS: 277.3, 279.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C(O[N:26]1N=[N:33][C:28]2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([NH:33][CH2:28][C:27]#[N:26])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(Sc2ccccc2Br)CCCCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1(Sc2ccccc2Br)CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2bromophenyl)sulfanyl]cyclohexanecarboxylic acid (77 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and aminoacetonitrile hydrochloride (33 mg, 0.35 mmol) in DMF (3 mL) was added Et3N (0.1 mL, 0.72 mmol). The mixture was stirred overnight, then partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with water, 1 M NaOH and brine, then dried over MgSO4 and concentrated to give 1-[(2-bromophenyl)sulfanyl]-N-(cyanomethyl)cyclohexanecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]([CH3:60])([CH3:59])[CH2:57][OH:58].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:55][C:56]([CH3:60])([CH3:59])[CH2:57][OH:58])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-benzoic acid (100 mg, 0.35 mmol) 3 in DMF was treated with DIPEA (0.3 mL, 1.76 mmol) followed by HATU (279 mg, 0.7 mmol). The mixture was stirred at room temperature for 10 minutes, then 2-amino-2-methyl-propan-1-ol, (CAS-124-68-5) (0.07 mL, 0.7 mmol) was added and continue stirred at room temperature overnight. Saturated sodium bicarbonate was added, and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. The crude was purified by Prep HPLC to give 15 mg of 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)benzamide 4. LC/MS (ESI+): m/z 356 (M+H). 1H NMR (400 MHz, DMSO) δ 8.55 (t, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.44 (d, J=7.1 Hz, 1H), 8.18 (t, J=8.8 Hz, 1H), 7.82 (d, J=24.4 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 4.87 (t, J=6.0 Hz, 1H), 3.58 (d, J=5.8 Hz, 2H), 2.07 (s, 2H), 1.36 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:33][C:34]3[CH:40]=[C:39]([C:41]([O-])=[O:42])[CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][CH:27]=1)#[N:25]>>[OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([NH:20][C:41]([C:39]4[CH:38]=[CH:37][C:35]5[N:36]=[C:32]([C:29]6[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=6)[NH:33][C:34]=5[CH:40]=4)=[O:42])=[CH:19][C:13]=3[N:12]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Product: N#Cc1ccc(-c2nc3ccc(C(=O)Nc4ccc5[nH]c(-c6ccc(N(CCO)CCO)cc6)nc5c4)cc3[nH]2)cc1

Procedure:
Compound 293 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O3: 558.22; found: 557.99.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:15]([CH3:14])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CN
Product: CN1Cc2cc(Br)ccc2C1=O
Temperature: 90 °C
Yield: 99.7 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90° C.) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). 1H NMR (500 MHz, CDCl3) δ ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57-7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 226.3.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[C:21](Cl)([Cl:23])=[S:22].[Cl-].[Ca+2].[Cl-]>O.C(Cl)(Cl)Cl>[Cl:23][C:21]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[S:22]
Reactant: COc1ccc(SC(=O)c2ccc(O)cc2)cc1
Reactant: S=C(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(SC(=O)c2ccc(OC(=S)Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.01 g) in 2 ml of water was added to a cool (10° C. or below) solution of 5.50 g of S-(4-methoxyphenyl) 4-(hydroxy)thiobenzoate and 2.42 ml of thiophosgene in 75 ml of chloroform. Vigorous stirring was continued for 2 hours at room temperature and the filtered solution treated with calcium chloride for a further 30 minutes. Evaporation of the filtered solution and chromatography of the residue on silica gel using hexane/ethyl acetate mixtures as eluant gave 2.75 g of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][NH2:20]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][N:20]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1ccccn1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccn1
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of phthalic anhydride 4 (5.0 g, 33.7 mmol) and pyridylethylamine (4.04 mL, 33.7 mmol) were heated together at 100° C. for 4 h. The resulting red oil upon cooling to room temperature yielded an off-white solid that was filtered and dried under vacuum to provide 5 as a white solid (5.6 g, 66%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:28][C@@H:26]([C:23]4[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=4)[CH3:27])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4cnc(C)nc4)c3C2)nc1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (120 mg, 0.46 mmol) and (R)-1-(2-methylpyrimidin-5-yl)ethanamine (120 mg, 0.87 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (500 μL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-prep HPLC (100×20.2 mm, C18 column; 30-55% CH3CN-water [10 mM Et2NH]) to give a light color solid. LC-MS: 362.4 [M+H]+;
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C#N)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.5 %

Procedure:
4-Cyanoaniline (0.189 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.141 g, 0.297 mmol, 56%).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)N(C)C(=O)CS2
Reactant: Nc1ccccn1
Product: Cc1c(-c2ccc3c(c2)N(C)C(=O)CS3)nc2ccccn12
Yield: 67.9 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (2.1 g) was prepared in the substantially same manner as that of Example 4 from 6-(2-bromopropionyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (3.14 g) and 2-aminopyridine (2.85 g).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:17][CH:18]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (D3) (2.27 g, 5.27 mmol) was dissolved in dichloromethane (10 ml), treated with trifluoroacetic acid (5 ml) and stirred at room temperature under argon for 2 hours. The solvent was removed in vacuo and the residue dissolved in methanol and passed down an SCX column (10 g) eluting with methanol followed by 0.88 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (1.57 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([N:21](C)[C:22](=[O:40])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26](C(OC(C)(C)C)=O)[CH:25]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.C(OC1C=C2C(=CC=1)NC=C2)C1C=CC=CC=1.BrC1C(N(C)C(=O)C=1C1C2C(=CC=CC=2)N(C(OC(C)(C)C)=O)C=1)=O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([NH:21][C:22](=[O:40])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C(c2c[nH]c3ccc(OCc4ccccc4)cc23)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: CC[Mg]Br
Agent: CN1C(=O)C(Br)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c[nH]c3ccc(OCc4ccccc4)cc23)=C1c1c[nH]c2ccccc12
Temperature: 50 °C

Procedure:
The 2-(5-benzyloxy-1H-indol-3-yl)-3-(1-tert.-butoxycarbonyl-1H-indol-3-yl)-N-methylmaleinimide used as starting material is prepared as follows: A solution of 20 mmol ethyl magnesium bromide in 30 ml tetrahydrofuran is mixed with a solution of 4.46 g (20 mmol) 5-benzoxyindole in 20 ml tetrahydrofuran. The reaction mixture is maintained at 50° C. for 1 hour and then, within the course of 1 hour, a solution of 3.0 g (7.4 mmol) 2-bromo-3-[1-tert.-butoxycarbonyl-1H-indol-3-yl]-N-methylmaleinimide (Tetrahedron, 44, 2887/1988) in 40 ml tetrahydrofuran added dropwise thereto. The reaction mixture is heated under reflux for 2 hours, allowed to cool and then decomposed with a saturated aqueous solution of ammonium chloride. The reaction product is extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is flash chromatographed on silica gel (Merck Type 7734) using dichloromethane as elution agent. After elution of unreacted starting material, the desired product is obtained by evaporation of the appropriate fractions and stirring the red residue with a little toluene. There are obtained 1.3 g (32% of theory) of red crystals; m.p. 123° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].NC(C)(C)C#N>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([CH2:25][OH:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Agent: CC(C)(N)C#N
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1CO
Yield: 24 %

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-yn yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.09 g) was reacted with 2-amino-2-methylpropionitrile similar to as described in Example 2 to afford 20.8 mg of 9-fluoro-3-(hydroxymethyl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 440 (M)+. 1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.07 (s, 1H), 7.03 (d, J=10.5 Hz, 1H), 5.50 (s, 1H), 5.10-4.93 (m, 2H), 4.64-4.46 (m, 2H), 1.70 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:18][S:19]([C:22]1[N:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[CH:24][N:23]=1)(=O)=O.[OH-].[Na+]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]2[C:28]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([S:19][CH3:18])[N:27]=2)=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: COC1CNN(C(=O)Cc2ccc(F)cc2)C1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(SC)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Fluorophenyl)-1-(4-methoxy-pyrazolidin-1-yl)-ethanone, 47, (7.67 g, 32.2 mmol) and 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (9.11 g, 48.3 mmol) are dissolved in dichloromethane (150 mL). A 0.5 N aqueous solution of sodium hydroxide (150 mL) is added steadily via addition funnel and the mixture is stirred vigorously at room temperature for 4 hours. The reaction is diluted with 5% aqueous sodium carbonate solution (1 L). The mixture is extracted with dichloromethane (6×200 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to give a red oil. The crude material is purified by over silica (1:1 to 1:3 hexane/ethyl acetate to 100% ethyl acetate) to afford 10.3 g of the desired product as a brown, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]([O:20][CH3:21])=[C:13]([C:16]([O:18]C)=[O:17])[NH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:6]([O:22][C:11]1[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=1[O:20][CH3:21])[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1[nH]cc(C(=O)NCc2ccc(F)cc2)c(=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)ncc(C(=O)NCc2ccc(F)cc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
The compound 28 (900 mg, 2.12 mmol) was dissolved in methanol (8 ml), and a 2N aqueous sodium hydroxide solution (4 ml) was added. The solution was stirred at room temperature for 2 hours, 2M hydrochloric acid (3 ml) was added, and crystals were collected by filtration. 4-Benzyloxy-5-(4-fluoro-benzylcarbamoyl)-3-methoxy-pyridine-2-carboxylic acid 29 (474 mg, 54%) was obtained as a colorless crystal.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:8](=[O:23])[C:7]=1[CH2:24][N:25]([CH2:36][C:37]([O:39][CH3:40])=[O:38])S(C1C=CC(C)=CC=1)(=O)=O)=O)C.C[O-].[Na+].Cl>CO>[CH3:40][O:39][C:37]([C:36]1[N:25]=[CH:24][C:7]2[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[CH:10]=[CH:11][C:6]=2[C:4]=1[OH:3])=[O:38]
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reaction time: 8 h
Yield: 90.1 %

Procedure:
1-(2,4-Dimethoxy-benzyl)-3-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid ethyl ester (4.2 g, 7.34 mmol) was dissolved in MeOH (160 mL). NaOMe solution (5 mL, 22 mmol, 25 wt % in MeOH) was added, and the mixture was stirred overnight. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-80% EtOAc/hexanes+2% AcOH) to give 2.45 g of the title compound as a yellow solid. MS: (+) m/z 371.28 (M+1).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: C1CCNC1
Product: Brc1cnc(Nc2ccc(CCN3CCCC3)cc2)nc1Nc1ccccc1

Procedure:
Using an analogous method to that described in Example 32, but starting from 4-anilino-5-bromo-2-[4-(2-hydroxyethyl)anilino]pyrimidine (Method 11) and pyrrolidine, the product was obtained. MS (MH+): 438.1, 440.1; HPLC (RT): 5.64.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#N.[PH2]([O-])=[O:13].[Na+].N1C=CC=CC=1>O.C(O)(=O)C.[Ni]>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:13])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 88.8 %

Procedure:
To a solution of 6-cyanoindole (15.0 g) and sodium hypophosphite (90 g) in water (326 mL), acetic acid (326 mL), and pyridine (652 mL) was added Raney Nickel catalyst and the mixture stirred at 45° C. for 45 minutes. The mixture was filtered through Celite and the filtrate extracted with ethyl acetate (3×500 mL). The extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from a mixture of dichloromethane and hexanes to provide 13.6 g (89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[N:27]=2)[C:19]1=[O:33])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].[CH3:41][O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].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.[Fe+2]>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@@H:8]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)[N:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:48][CH2:47][C:46]3[CH:49]=[CH:50][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[N:27]=2)[C:19]1=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCc3cccc(Br)n3)C2=O)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Temperature: 110 °C

Procedure:
To a stirred solution of 20-11 (0.075 g, 0.142 mmol) in toluene (3 mL) was added Pd(DBA)2 (0.0041 g, 0.0071 mmol), DPPF (0.0039 g, 0.0071 mmol), and NaOt-Bu (0.0163 g, 0.170 mmol) followed by p-methoxybenzylamine (0.0204 mL, 0.156 mmol). The resulting solution was heated at 110° C. for 2 hours. The solution was cooled and the solvent was removed in vacuo. The product was purified by silica gel chromatography (10% EtOH/EtOAc) to give (20-12.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#N)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].[PH2]([O-])=[O:21].[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]=[O:21])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: O=[PH2][O-]
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(C#N)ccc12
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(Cl)ccc2cc(C=O)ccc12
Temperature: 100 °C

Procedure:
(2-Chloro-6-cyano-naphthalen-1-yl)-acetic acid ethyl ester (1.39 g, 5.07 mmol) is dissolved in a mixture of water (17 ml), pyridine (33 ml) and glacial acetic acid (17 ml). Sodium hypophosphite (4.30 g, 40.62 mmol) and Raney nickel (3.2 g) are then added at RT. The reaction mixture is heated to 100° C. for 1 h. TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT and filtered through Celite. After addition of silica gel, the solvents are removed on a rotary evaporator. Purification by FCC (hexane/EtOAc 5:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.17 (t, J=8 Hz, 3H), 4.10 (q, J=8 Hz, 2H), 4.24 (s, 2H), 7.52 (d, J=10 Hz, 1H), 7.82 (d, J=10 Hz; 1H), 7.94-7.98 (m, 2H); 8.26 (s, 1H), 10.09 (s, 1H). ES−-MS: 275.2, 277.3 [M−H]−.