Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](O)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:17][CH3:18].P(Cl)(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:17][CH3:18])[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2c(O)ncnc2cc1OCCCCl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCCl
Temperature: 125 °C
Yield: 78 %

Procedure:
To a solution of the intermediate from Step 4 (3.00 g, 11.16 mmol) in toluene (30 mL) in a pressure vessel was added phosphorous oxychloride (8 mL). The mixture was heated to 125° C. for 5 hours. Completion of the reaction was monitored by LCMS. The mixture was concentrated to dryness and excess ethyl acetate was added. The solution was washed with water and brine and was dried (Na2SO4) and concentrated to afford the pure compound 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (2.51 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.75 (t, 2H), 2.25 (q, 2H). LC-MS (ESI)m/z 287 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[Cl:32])[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:36]=[C:37]([F:41])[C:38]([F:40])=[CH:39][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 68.9 %

Procedure:
A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (121 mg, 0.20 mmol), 10% palladium-activated carbon (85 mg), ethyl acetate (10 mL), and methanol (1 mL) was stirred under a hydrogen atmosphere at room temperature for 19 h. The Pd catalyst was filtered off and the filtrate was concentrated to afford 1-(3-amino-4-chlorobenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (78 mg, 68%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>>[CH:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
At 0° C., methanesulfonyl chloride (9.51 ml, 0.123 mol) was added to a solution of 4-hydroxybenzaldehyde (15 g, 0.123 mol) in pyridine (12.91 ml, 0.160 mol). The reaction mixture was stirred at 0° C. for 3 h and left at room temperature for 16 h. It was given onto conc. hydrochloric acid/ice (200 ml/200 ml). The mixture was extracted with ethyl acetate (4×300 ml). The combined organic layers were washed with a 5% aqueous solution of sodium hydrogen carbonate (3×200 ml) and brine (100 ml). They were dried over magnesium sulphate. The solvent was removed in vacuo to give 22.87 g of crude methanesulfonic acid 4-formylphenyl ester, which was used in the next step without further purification.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:19](=[O:21])=[O:20]>C1COCC1>[Cl:6][C:7]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([Cl:18])[CH:15]=[CH:16][C:17]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CCOC(=O)c1c(Cl)cccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexane, 16.5 ml) was added to a solution of ethyl 2,6-dichlorobenzoate (6.89 g) in THF while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and poured onto solid carbon dioxide pellets. The mixture was acidified to pH1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of cyclohexane and ether to give 2,4-dichloro-3-ethoxycarbonylbenzoic acid (4.35 g) as a white solid mp 168° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:45]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: COC1(Cc2ccccc2F)CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.025 mmol, 12.4 mg), HCl salt of 3-(2-fluorobenzyl)-3-methoxycyclohexanamine (0.025 mmol, 6.8 mg), HATU (0.025 mmol, 9.5 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-methoxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.60 (m, 1H), 8.47 (d, 1H), 7.96 (d, 2H), 7.62 (m, 1H), 7.47 (d, 2H), 7.22 (m, 1H), 6.94 (m, 1H), 6.76 (dd, 1H), 4.50 (s, 2H), 3.85 (s, 2H), 3.78 (s, 2H), 1.46 (s, 9H); MS 406 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:27](=O)[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCCC1

Procedure:
using ethyl 2-chloro-5-ureidobenzoate and ethyl cyclohexanone-2-carboxylate there is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclohexen-1-yl]ureido}-benzoate, m.p. 119°-122° C.,
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>C1COCC1>[CH3:5][Si:4]([CH2:3][C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)CCl
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CC1(O)CCCCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A flask was charged with 27.9 g of magnesium and 250 ml of THF, to which a solution of 135 g of chloromethyltrimethylsilane diluted with 150 ml of THF was added dropwise at 50° C. The addition was followed by one hour of stirring at 65° C., after which 98.1 g of cyclohexanone was added dropwise below 20° C. After one hour of stirring at room temperature, an aqueous solution of ammonium chloride was added for hydrolysis. This was followed by ordinary post-treatments. Upon vacuum distillation, there was obtained 141.6 g (yield 76%) of 1-trimethylsilylmethylcyclohexanol.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=442.99.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CO.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=2)=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)cc1

Procedure:
4.6 g (15.00 mmol) 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine are added to 12 mL methanol and 50 mL 1,4-dioxane. Then the mixture is charged with 2.40 g (17.3 mmol) p-tolyl-boronic acid, 0.1 g (0.15 mmol) bis(triphenyphosphine)-dichloropalladium and 16.5 mL (33.0 mmol) of a 2N aq. Na2CO3 solution. The reaction mixture is stirred at reflux for 2 h. Then the solvent is removed in vacuo to some extent and the residue is diluted with EtOAc and water. The organic layer is sequently washed with 50 mL half sat. Na2CO3 solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with DIPE and PE to receive a precipitate which is filtered and dried to yield the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][S:25][C:26]1[N:30]=[CH:29][NH:28][N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([N:28]1[CH:29]=[N:30][C:26]([S:25][CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[N:27]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1nc(SCC2CCCCO2)n[nH]1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cnc(SCC2CCCCO2)n1

Procedure:
11.6 g (85 mmol) of diethylcarbamoyl chloride and a spatula-tipful of dimethylaminopyridine were added to a solution of 200 ml of absolute tetrahydrofuran and 17.0 g (85 mmol) of 3-(tetrahydropyran-2-yl)methylthio-1,2,4-triazole (step b). 9.5 g (94 mmol) of triethylamine were then added dropwise and the mixture was heated under reflux for 2 hours. The solvent was distilled off and the residue was purified by chromatography over silica gel. 11.2 g (44% of theory) of a viscous clear oil were obtained. (1H-NMR (CDCl3; δ in ppm): 8.75 (s,1H); 4.00 (d,1H); 3.70-3.50 (bm,5H); 3.40 (dt,1H); 3.25 (d,2H); 1.85 (d,1H); 1.80 (d,1H); 1.65-1.45 (m,4H); 1.30 (t,6H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C4CCCCO4)=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.C1(S)C=CC=CC=1.Cl>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(OC4CCCCO4)cc3)c3cc(Br)cnc32)cc1
Agent: Cl
Agent: Sc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
575 g (1.09 mmol) of 5-bromo-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 250 ml of dichloromethane. To this solution was added 2.50 g (3.53 mmol) of PS-thiophenol (Argonaut Technologies) and 1.5 ml of a 2 M solution of hydrochloric acid in ether. The mixture was stirred at room temperature for 3 hours before the resin was filtered off, washing extensively with dichloromethane. The filtrate was evaporated to afford 389 mg (877 μmol, 81%) of 4-[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenol as a pale yellow solid. 1H-NMR (d6-DMSO) δ: 9.67 [1H] s, 8.52 [1H] d, 8.43 [1H] d, 8.11 [1H] s, 8.03 [2H] d, 7.58 [2H] d(m), 7.43 [2H] d, 6.89 [2H] d(m), 2.35 [3H] s. MS, m/z: 443 [MH+].
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: CNC
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottomed flask equipped with magnetic stir bar was charged with 1.7 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to −78° C. and 15 mL of anhydrous dimethylamine was slowly added. After 30 minutes the reaction was concentrated in vacuo and the residue was partioned between EA/H2O. The organic phase was dried, concentrated in vacuo to yield 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate as a clear amber oil which was used directly in the next step. Part B: 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid A 100 mL Fisher/Porter vessel was charged with 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate in 30 mL acetic acid with a catalytic amount of 10% Pd—C. The reaction was hydrogenated at 50 psi for 24 hours, filtered through Celite and concentrated in vacuo. The residue was azeotroped with toluene then concentrated in vacuo to afford 900 mg of 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=S)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH2:34]>C(O)C>[Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]=[C:11]1[NH:34][NH:33][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Solvent: CCO
Product: CCOC(=O)NNC1=Nc2cc([N+](=O)[O-])ccc2OC1(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 76.3 %

Procedure:
2,2-Bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (4.6 g) and ethyl hydrazinecarboxylate (2.88 g, 3.0 eq.) were suspended in ethanol (50 ml). The reaction mixture was refluxed for three days. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-80%) to give ethyl 2-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3-yl)hydrazine-1-carboxylate (4 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)#[N:2].N>CO.O=[Pt]=O>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(CC#N)c[nH]1
Agent: O=[Pt]=O
Agent: N
Solvent: CO
Product: CCOC(=O)c1cc(CCN)c[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the product obtained in Step F (7.45 g) in MeOH (1.5 L) there are added 223 ml of a 1.4N solution of NH3 in MeOH and PtO2 (5.2 g). The reaction mixture is placed under an atmosphere of hydrogen and is then stirred for 20 hours at ambient temperature. After filtration and evaporation to dryness, the residue obtained is purified on silica gel (SiO2: gradient CH2Cl2/MeOH with the addition of 1.4N NH3 in the MeOH) to yield the title product which is used directly in the next Step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([N:37]1[CH2:42][CH2:41][N:40]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:39][CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
1.0 Gram of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of DCC and 1.1 g of benzylpiperazine were suspended in 10 ml of dioxane and the suspension was stirred at 70° C. for 5 hours. After the reaction was completed, the solvent was removed by distillation and ether was added to the residue and crystals formed were removed by filtration. After the mother liquor was concentrated, the residue was dissolved in chloroform and the chloroform solution was washed with water and a saturated sodium chloride aqueous solution then dried with anhydrous sodium sulfate and the solvent was removed by distillation. Recrystallized from ethanol to obtain 330 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH2:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>[Ag]=O.C(OC(C)C)(C)C>[CH3:11][O:10][C:6]1[C:7](=[NH:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[NH:12])[CH:5]=1
Reactant: COc1cc(N)c(OC)cc1N
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: COC1=CC(=N)C(OC)=CC1=N

Procedure:
0.06 mole (10 g) 2,5-dimethoxy paraphenylene diamine is introduced into a liter of anhydrous isopropyl ether. 21 g silver oxide and 48 g anhydrous sodium sulfate are then added to the same. The resulting mixture is heated at reflux for 6 hours, while maintaining good agitation. After cooling the reaction mixture the sodium sulfate and the silver are filtered out and the filtrate is evaporated to dryness under vacuum. The dry residue which is the above diimine, after recrystallization from a benzene-petroleum ether mixture, yields pure 2,5-dimethoxy benzoquinone diimine having a melting point of 184°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(Cc1ccco1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 72.1 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-furfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Product: COC(=O)c1ccc2c(cnn2Cc2cc(Br)cc3cnn(CC(C)C)c23)c1
Yield: 65 %

Procedure:
Compound 26 was prepared following general method 3A, using compound 18 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 65%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:7]1[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]1=[O:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)C1CCCC(=CN(C)C)C1=O

Procedure:
Ethyl 2-oxo-cyclohexanecarboxylate (38 mg, 0.22 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (49 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 226.1 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C.C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:30]([CH3:29])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Reactant: CNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N(C)Cc3ccccc3)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.5 g) in ethanol (15 ml) was added N-methylbenzylamine (1.47 ml). The mixture was refluxed for 5 hours. The resulting suspension was dissolved in chloroform, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The obtained syrup was triturated in diisopropyl ether and filtered to afford 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(N-methyl-N-benzylamino)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.18 g).