Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2].Cl[C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:1]([N:3]([C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:23]=2[N:24]=[CH:25][N:26]=1)[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: CCN[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of (S)-benzyl 3-(ethylamino)piperidine-1-carboxylate (200 mg, 0.76 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (234 mg, 0.76 mmol) and DIEA (0.27 mL, 1.52 mmol) in DMF (3 mL) was heated to 100° C. for 4 h. The reaction was cooled to rt, diluted with ice cooled water (10 mL) and extracted with EtOAc (3×25 mL). The combined EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-10% EtOAc hexane) to afford the titled intermediate (300 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.95 (s, 1H), 7.58-7.57 (m, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39-7.29 (m, 5H), 5.12 and 5.09 (2s, 2H), 4.69-4.63 (m, 1H), 4.05-3.98 (m, 3H), 3.65-3.63 (m, 2H), 3.01-2.77 (m, 1H), 2.36 (s, 3H), 1.89-1.75 (m, 3H), 1.51-1.39 (m, 1H), 1.17 (t, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=534.
Reaction SMILES: N1CCCCC1.O[CH:8]1[CH2:13]SC(O)C[S:9]1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>>[NH2:16][C:15]1[S:9][CH:8]=[CH:13][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC#N
Reactant: OC1CSC(O)CS1
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccsc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Piperidine (20.7 ml) was added dropwise with stirring to a mixture of 2,5-dihydroxy-1,4-dithiane (17.5 g) and ethyl cyanoacetate (23.7 g). The mixture was stirred at room temperature for 4 hours and then allowed to stand overnight. It was filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, filtered and evaporated to dryness. The residue was triturated with light petroleum (b.p. 60-80° C.) containing a small amount of ethyl acetate. The gummy solid obtained was purified by silica gel column chromatography and the semi-solid product was triturated with water, filtered and washed with light petroleum (b.p. 60-80° C.) and dried to give the title product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]([CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Clc1cnccn1
Reactant: Oc1ccccc1
Product: c1ccc(OCC2CCC3CN(c4cnccn4)CCN3C2)cc1

Procedure:
A mixture of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 2-chloropyrazine were combined according to Preparation 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl) 217–219° C. HRMS calcd for C19H24N4O: 324.1945, found: 324.1981.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C@H:4]([OH:6])[CH3:5].[H-].[Na+].[NH2:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.O>O1CCOCC1.C(Cl)Cl>[NH3:2].[NH2:10][C:11]1[N:12]=[C:13]([O:6][C@H:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: C[C@@H](O)CN(C)C
Reactant: N#Cc1ncc(N)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](CN(C)C)Oc1nc(N)cnc1C#N
Product: N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 77.9 %
Yield: 1 %

Procedure:
(R)-1-(Dimethylamino)propan-2-ol (0.667 g, 6.47 mmol) was added dropwise to a suspension of NaH (60% in oil; 0.388 g, 9.71 mmol) in dioxane (16.2 mL) and stirred for 30 minutes. 5-Amino-3-chloropyrazine-2-carbonitrile (Intermediate I-2) (1.00 g, 6.47 mmol) was added in one portion and the mixture was heated at 90° C. for 14 hours. After cooling, water (200 mL) was added and the solution was extracted with Et2O (4×100 mL), dried over MgSO4, and the volatiles removed under vacuum. Gradient column chromatography eluting with MeOH: 1% NH3 in CH2Cl2, gave (R)-5-amino-3-((1-(dimethylamino)propan-2-yl)oxy)pyrazine-2-carbonitrile (0.558 g, 2.52 mmol, 39% yield) as a yellow solid.
Reaction SMILES: Cl.[NH:2]([C:6]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1)C(C)=O>CO>[NH2:2][C:6]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Reaction time: 8 h
Yield: 91.6 %

Procedure:
400 ml of 4 N hydrochloric acid in methanol were added dropwise at reflux temperature to 22.4 g of 7-acetamino-8-nitro-3,4-dihydro-2H-1,5-benzodioxepine in 2000 ml of methanol, then the mixture was boiled overnight. After evaporation, the residue was taken up in methylene chloride, washed with 2 N soda and twice with water, dried over sodium sulfate and again evaporated. The crude product was recrystallized from alcohol. 17.1 g (92.0% of theory) of 7-amino-8-nitro-3,4-dihydro-1H-1,5-benzodioxepine of melting point 125°-126° C. were obtained.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)C)C.C1(NC2CCCCC2)CCCCCC1.NC1SC=NC=1.C([O:53][C:54](=[O:57])[CH2:55]S)C>>[CH:23]1([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:55][C:54]([OH:53])=[O:57])=[CH:9][N:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCCC2)C2CCCCC2)s1
Agent: C1CCCC(NC2CCCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCCC2)C2CCCCC2)s1

Procedure:
[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid ethyl ester pre-pared as described in general procedure (A) using cycloheptyl-cyclohexylamine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]3)[CH:13]=2)OC1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=2[N:35]=1>[Pd]>[F:27][C:11]1[CH:10]=[C:9]([F:28])[C:8]([C:31]2[O:32][C:33]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:13][C:12]=1[C@:14]1([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:23])([CH3:24])[O:18][CH2:17][C:16](=[O:25])[NH:15]1
Reactant: FC(F)(F)c1ccc2nc(Cl)oc2c1
Reactant: CC1(C)COB(c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)OC1
Agent: [Pd]
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 73 %

Procedure:
In a manner analogous to that described in Example 19a), the palladium-catalyzed coupling of (R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate D1.1) and 2-chloro-6-(trifluoromethyl)benzo[d]oxazole yielded the title compound (73% yield) as a white solid. MS (ISP): m/z=491.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[C:13]1([C:6]2[CH:7]=[C:8]([C:10](=[O:12])[NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(C(=O)Nc2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 174 (0.334 g, 1.273 mmol) in 6 mL DMF was added PhNH2 (0.128 ml, 1.401 mmol), followed by BOP (0.620 g, 1.401 mmol) and TEA (0.355 ml, 2.55 mmol). The mixture was stirred for 1 h at room temperature and then poured into water. The product was extracted with ethyl acetate twice and the combined organic phases were washed with water and brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified by ISCO (24 g column, 0%-100% ethyl acetate in hexanes) to yield compound 175 (285 mg, 66%) a off-white solid.
Reaction SMILES: C(N)(N)=[O:2].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]1[N:29]=[CH:28][C:27]2[N:26]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:25]3[N:38]=[CH:39][CH:40]=[CH:41][C:24]=3[C:23]=2[CH:22]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH2:49]>C(Cl)(Cl)Cl.CO>[Br:20][C:21]1[N+:29]([O-:49])=[CH:28][C:27]2[N:26]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[C:25]3=[N+:38]([O-:2])[CH:39]=[CH:40][CH:41]=[C:24]3[C:23]=2[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2cccnc21
Reactant: O
Reactant: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2ccc[n+]([O-])c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of hydrogen peroxide-urea adduct (4.2 g, 45 mmol) in chloroform (37 mL) was added trifluoroacetic anhydride (6.3 mL, 44.4 mmol) dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for 5 minutes and then to this was added 6-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (2.1 g, 5.6 mmol) as a solution in chloroform (15 mL). Note: an exotherm is observed upon addition of the substrate. The reaction mixture was stirred at ambient temperature for 10 minutes and then at 50° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, treated with saturated sodium thiosulfate solution (20 mL), and diluted with water (50 mL) and methanol (10 mL). The layers were separated and the organic layer was washed with 0.5N hydrochloric acid (50 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 80 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as a pale yellow solid, which was used in the next step without any further purification (1 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N@@:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:10])=[O:9])=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].[I-].[Na+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:9])=[O:10])[C:26](=[O:27])[N:25]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[O:4]
Reactant: COC(=O)C1C[N@@]1S(=O)(=O)c1ccccc1Cl
Reactant: O=C=Nc1ccccc1Cl
Agent: COC(=O)C1C[N@]1S(=O)(=O)c1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, (S)-1-(2-chloro-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester was reacted with 2-chlorophenylisocyanate and sodium iodide to give (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester as a colorless foam.
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:19][C:20]([CH3:23])([O-])[CH3:21].[K+].[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>CN(C=O)C>[C:6]([O:5][C:3]([CH:2]([C:1]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C@@H:30]([CH2:19][CH:20]([CH3:23])[CH3:21])[C:28]([O:27][CH2:26][C:25]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:29])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 89 %

Procedure:
Benzyl tert-butyl malonate (24.9 g, 99.6 mmol) was dissolved in DMF (60 ml) and added portion wise with potassium tert-butoxide (13.4 g, 120 mmol) at 0° C. under stirring. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and dropped in 1 hour with the solution of the Example 3-a compound (28.4 g, 99.6 mmol) dissolved in DMF (60 ml). After the reaction mixture was stirred at 5° C. overnight, it was added with AcOEt (2 l) and washed with a saturated aqueous solution of NaCl, 1N-HCl, a saturated aqueous solution of NaHCO3 and then the saturated aqueous solution of NaCl two times respectively. The organic layer was dried over anhydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 750 g, elution with the mixed solvent; n-hexane:AcOEt=20:1), giving the title compound (40.0 g, 89%) of a colorless oil.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[ClH:16].C(O)C>COCCOCCOC>[Cl:16][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=1)=[O:15]
Reactant: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cl
Solvent: CCO
Solvent: COCCOCCOC
Product: NS(=O)(=O)c1cccc(C(=O)CCl)c1

Procedure:
9.5 g of 3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) with 37% HCl in diethylene glycol dimethyl ether and worked up. Colorless crystals, melting point: 118° C. (from a small amount of ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH:27][C:13](=[O:15])[C@H:12]([NH:11][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[C:7]([Cl:8])[C:2]=2[Cl:1])[C@@H:16]([OH:18])[CH3:17])=[O:25])=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)NNC(=O)c1ccc(Cl)cc1
Yield: 52.3 %

Procedure:
(2R,3S)-2-(2,3-dichloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.0 g, 3.46 mmol) and 4-chlorobenzohydrazide (590 mg, 3.46 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (800 mg, 52%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 10.4 (br s, 2H), 7.98 (d, J=8 Hz, 2H), 7.61 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 6.84 (d, J=8 Hz, 1H), 6.18 (d, J=6 Hz, 1H), 5.0 (br s, 1H), 4.31-4.38 (m, 1H), 4.18-4.2 (m, 1H), 1.36 (d, J=6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:33]>CCOC(C)=O.O1CCOCC1>[ClH:33].[Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCN(C(=O)OC(C)(C)C)CC3)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCNCC3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 7-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl }-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.280 g, 0.52 mmol) was dissolved in EtOAc (15 mL). 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at rt under N2. After 1 h, a white solid precipitated from the solution. The precipitate was collected by filtration. Pure 2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide hydrochloride was obtained after recrystallization from 3:1 CH3OH:Et2O (20 mL), as a white solid (0.220 g) in 94% yield. 1H NMR (400 MHz, CD3OD) δ 2.4, 3.22-3.28, 3.49-3.59, 5.7-5.78, 6.88, 7.02, 7.35, 7.54; MS (ESI+) for C18H19BrN4OS m/z 420.8 (M+H)+.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:11][CH2:12]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CC[C@H](OS(C)(=O)=O)CC2)CC1=O

Procedure:
109 g of mesyl chloride in 250 ml THF are added dropwise to 150 g (trans)-1-hydroxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane and 162 ml triethylamine in 2300 ml THF in such a way that the temperature does not exceed 35° C. After 25 min the suspension is filtered and washed with 300 ml THF. The filtrate is evaporated down in vacuo at 40° C. to a total mass of 520 g. 230 ml ethyl acetate are added to the suspension. After 15 min the mixture is filtered and the precipitate is washed with 230 ml of ethyl acetate and 150 ml of methyl-tert-butyl ether. After drying, 153.1 g product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:13]([F:27])=[CH:12][N:11]=1>>[CH3:26][O:25][C:18]1[C:17]([NH:16][C:14]2[C:13]([F:27])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[CH:22][CH:21]=[C:20]([O:23][CH3:24])[N:19]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1
Reactant: Nc1cccc(O)c1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.98 (bs, 2H), 8.20 (d, 1H, J=5.4 Hz), 7.72 9m, 1H), 6.90 (t, 1H, J=7.8 Hz), 6.81 (m, 2H), 6.42 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H); LCMS: purity: 94%; MS (m/e): 358 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])[CH2:20][C:19]2=[O:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-methanesulfonylphenyl)piperidin-3-ol (0.39 g, 0.77 mmol) obtained in Step 5 in 3 ml of dimethylsulfoxide (DMSO), was added 0.4 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.4 g, 2.51 mmol) was added to the reaction mixture, which was then stirred for 2 hours. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 155 mg of the titled compound as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Product: C[C@@H](c1ccc(C#Cc2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-[(S)-1-(4-ethynyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 5-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 31. LC-MS (Method 1): tR=3.46 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[C:13]([NH2:17])(=[O:16])[CH2:14]O>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]1[NH:17][C:13](=[O:16])[CH2:14][O:6]1
Reactant: NC(=O)CO
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1NC(=O)CO1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with glycolamide; LC-MS: tR=0.41 min; [M+H]+=224.31.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COCCN
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCNC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-methanesulphonyl-piperidine-4-one (182 mg; prepared from N—BOC-piperidone by reaction of piperidone-4-one TFA salt with methane sulphonyl chloride), stirring in anhydrous 1,2-dichloroethane (6 ml) was added 2-methoxyethylamine (90 μl) followed by glacial acetic acid (62 μl). Sodium triacetoxy borohydride (284 mg), was added in aliquots over 30 minutes and the reaction mixture stirred for 12 hours at room temperature, then diluted with dichloromethane (40 ml), washed with 50% NaHCO3 solution and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by silica flash chromatography to give 1-methanesulphonyl-piperidin-4-yl-2-methoxy-ethylamine (148 mg), as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[OH:22][C:23]1C(C)=CC(C#N)=CC=1OC>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[O:22][CH3:23])[CH2:4][O:3]1
Reactant: COc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: COc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a beige oil (1.16 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-3-methoxy-5-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.65 min, [M+H]+=311.0.