Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
500 ml of 3 N HCl in dioxane was added to the mixture of 40 g of the product of Step 1 in 500 ml of DCM and the solution was stirred overnight at RT. The solvent was evaporated, and the residue was washed with Et2O (1000 ml) to afford 6-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one hydrochloride (30 g, 95% yield). 1H-NMR (300 MHz, DMSO-d6) δ: 10.17 (s, 1H), 7.28-7.23 (m, 2H), 6.88-6.86 (m, 1H), 3.90 (s, 2H), 2.89-2.84 (m, 2H), 2.53-2.42 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28]
Reactant: Cc1c(C2=NN(Cc3ccccc3Cl)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccccc3Cl)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic Acid tert-butyl ester (61 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.94 (t, 1H), 7.83 (t, 1H), 7.45 (m, 6H), 6.88 (dt, 1H), 6.51 (dd, 1H), 5.19 (bs, 2H), 4.43 (s, 2H), 2.02 (s, 3H) ppm. MS calculated for C25H19FClN3O4S—H: 510, observed: 510.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:42]>C(OCC)(=O)C>[NH2:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1ccc2c(Cl)cnnc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: Nc1cnnc2cc(CN3CCN(S(=O)(=O)C=Cc4ccc(Cl)s4)CC3=O)ccc12
Temperature: 120 °C
Yield: 35.8 %

Procedure:
1-(4-Chlorocinnolin-7-ylmethyl)-4-[2-(5-chlorothiophen-2-yl)-ethenesulfonyl]-piperazin-2-one (0.06 g, 0.12 mmol) is treated with phenol (0.20 g) and ammonium acetate (0.2 g, 2.6 mmol) and heated to 120° C. for 45 minutes. The reaction mixture is cooled, diluted with ethyl acetate and washed with 1 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (20% aqueous TFA (0.1%)/acetonitrile to 100% acetonitrile). Fractions containing the desired product are lyophilized to obtain the title compound (0.02 g, 0.043 mmol). MS m/z: [M+H]+=464; 1H NMR (CD3OD, 300 MHz) δ8.6 (s, 1H), 8.4 (d, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 7.1 (d, 1H), 6.8 (d, 1H), 4.9 (s, 2H), 4.05 (s, 2H), 3.6 (m, 4H).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](O)=[O:12])[C:4]=2[O:3]1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCCl>[F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([Cl:22])=[O:12])[C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1cccc2c1OC(F)(F)O2
Yield: 106 %

Procedure:
2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid (15.0 g) was dissolved in 1,2-dichloroethane and N,N-dimethylformamide and thionyl chloride (10.6 g) added. The mixture was heated under reflux for 1 hour, and the solvent evaporated in vacuo. The residue was dissolved in toluene and re-evaporated to yield 2,2-difluoro-1,3-benzodioxol-4-oyl chloride (17.35 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1.[C:28]([O:32][C:33](=[O:42])[NH:34][C@@H:35]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[C:28]([O:32][C:33](=[O:42])[NH:34][C@@H:35]([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:36][NH:37][C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](CNc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F)NC(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 52 %

Procedure:
Potassium carbonate (139 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (60 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (S)-tert-butyl(1-amino-4-methylpentan-2-yl)carbamate (76 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13.5 hours. The reaction solution was adjusted to room temperature and an insoluble precipitate was removed. Subsequently, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), and a white solid of (S)-tert-butyl(1-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-4-methylpentan-2-yl)carbamate (50 mg) was thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][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][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:53])=[CH:45]1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:40][CH2:41][CH2:42][CH2:43][N:44]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH3:53])=[CH:45]5)=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: Cc1cn(CCCCBr)c2ccccc12
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCn4cc(C)c5ccccc54)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.149 g of 1-(4-bromobutyl)-3-methyl-1H-indole are reacted. The title compound is obtained as a colourless oil. Rf=0.21 (2:1 EtOAc-heptane); Rt=6.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][O:15]C)[CH2:9]2)=[CH:4][CH:3]=1>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC=C1CCCC(c2ccc(Cl)cc2)C1
Solvent: O=CO
Solvent: O
Product: O=CC1CCCC(c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
Crude C5 (1.25 g from the preceding step, ≦4.8 mmol) was dissolved in aqueous formic acid (3 M, 2.0 mL) and the mixture was refluxed for 2 hours. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate; the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptanes) afforded the title compound as an oil, presumed by 1H NMR to be a roughly 4:1 mixture of the two stereoisomers. Yield: 338 mg, 1.52 mmol, 32% over two steps. GCMS m/z 222 (M+). 1H NMR (400 MHz, CDCl3) δ [9.65 (d, J=1.4 Hz) and 9.79 (br s), total 1H], 7.25-7.30 (m, 2H), 7.12-7.18 (m, 2H), 1.21-2.66 (m, 10H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.[ClH:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[ClH:30].[C:44]([C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][CH2:33][NH:32][C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])[CH2:41][CH2:40]1)#[N:45]
Reactant: COC[C@@H]1OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H]1c1ccc(F)c(F)c1
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-methoxymethyl-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (195 mg, 0.48 mmol) in dry tetrahydroftirin (3 mL) was added 2-[1-(3-aminopropyl)piperidin-4-yl]benzonitrile dihydrochloride (134 mg, 0.48 mmol) (see Example 3) followed by N,N-diisopropylethylamine (167 μL, 0.96 mmol). The reaction mixture was stirred at room temperature for 20 h when the reaction was diluted with ethyl acetate (50 mL), washed with 10% aqueous sodium carbonate solution (6×25 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to afford an oil. The hydrochloride salt was prepared by standard procedures to provide (4S,5R)-4-(3,4-difluorophenyl)-5-methoxymethyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyanophenyl)piperidin-1-yl]propyl}amide hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[C:3]=1[F:20].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[C:3]=1[F:20]
Reactant: COC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nccc(-c2ccc(Br)c(F)c2F)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (800 mg, 2.34 mmol) in MeOH (10 mL) was added NaOH (935 mg, 23.38 mmol) in Water (10 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was evaporated under reduced pressure and the residue obtained was adjusted to pH ˜3 by adding 1.5N HCl solution. The product was extracted with dichloromethane and the layers were separated. The organic phase was dried over Na2SO4, and concentrated under reduced pressure to afford 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinic acid (700 mg, 2.133 mmol, 91% crude yield) as an off-white solid which was carried on without further purification. LC/MS (ESI) m/e 330.0 [(M+2H)+, calcd for C13H10BrF2NO2 330.1]; LC/MS retention time (method C): tR=1.34 min.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH2:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([CH:21]3[CH2:20][CH2:19][N:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: CCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (23 mmol), 4-(1-propyl-piperidin-4-yl)-benzoic acid hydrochloride (23 mmol), HOBT (23 mmol), WSCD (23 mmol) and triethylamine (23 mmol) are dissolved in DMF (50 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 198-200° C., Rf=0.34 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1.[C:17]([C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:16])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([F:10])[CH:9]=2)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cn1
Agent: Cl
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cn1
Yield: 78.7 %

Procedure:
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide HCl salt (50 mg, 0.18 mmol) was reacted with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (37 mg) to give the title compound (60 mg, 79%) after purification by column chromatography (Hex/EtOAc=1/2).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: O=C(O)c1ccccc1N1CCNCC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1N1CCNCC1
Reaction time: 16 h
Yield: 63 %

Procedure:
2-Piperazin-1-yl-benzoic acid (1.000 g, 4.89 mmol) is suspended in 10 mL of MeOH. To this is added 5 mL of conc. H2SO4. The mixture is stirred for 16 h resulting in a white precipitate. An additional 5 mL of H2SO4 is added with an additional 10 mL of MeOH. The reaction volume is increased by an additional 200 mL of MeOH and 60 mL of H2SO4 and the mixture is stirred an additional 2 h and then heated at reflux for 12 h. The reaction volume is then reduced to approximately 175 mL and applied to an ion exchange column, eluting with 5×200 mL of 10% NH3/MeOH and then the product fractions are concentrated. The eluent is co-evaporated with toluene to remove residual water to give 0.667 g of 2-piperazin-1-yl-benzoic acid methyl ester in 63% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:2]1.[Na].Cl.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C.C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]2=[O:16])=[CH:2]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)N1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1NC(c2c[nH]c3ccccc23)C(=O)N1CCCN1CCCCC1
Reaction time: 18 h

Procedure:
5-(Indol-3-yl)hydantoin (8.6 g, 0.04 mole) in 200 ml of DMF was added to a solution of sodium (1.84 g, 0.08 mole) in 150 ml of anhydrous C2H5OH. N-(3-Chloropropyl)piperidine hydrochloride (7.9 g, 0.04 mole) was added and the mixture was heated to reflux with stirring for 18 hours, filtered and concentrated in vacuo to dryness. The concentrate was crystallized from aqueous methanol and twice recrystallized from aqueous DMF, yield 1.7 g, mp 233°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:21][CH2:22][C:23](O)=[O:24].C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCCl>[Cl:21][CH2:22][C:23]([NH:20][C:19]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[N:13][C:12]=2[N:18]=1)=[O:24]
Reactant: O=C(O)CCl
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)CCl)nc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 50 ml of 1,2-dichloroethane is boiled on a steam bath until the distilling vapors reach a temperature of 83° C. The suspension is cooled to room temperature and 1.6 g of chloroacetic acid and 2.6 g of carbonyldiimidazole are added sequentially. The mixture is stirred at room temperature for 3 hours and the resulting solution is immediately chromatographed over 150 g of silica gel. The crude product is eluted with a 99/1 chloroform/methanol mixture. Trituration of this with ether gives pure 2-chloro-N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]acetamide, decomposing above ca 170° C.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+].CCOCC>C1(C)C=CC=CC=1>[Br:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Yield: 61.5 %

Procedure:
A suspension of 2,5-dibromo-3-nitrobenzoic acid (10.76 g, 0.0331 mol) in toluene (100 mL) was placed under argon, treated with 2-chlorobenzylamine (14.06 g, 0.0993 mol) and the mixture was brought to reflux. A clear, red solution resulted and the solution was refluxed for 24 hours, cooled, poured into 5% sodium hydroxide solution (600 mL) and ether (100 mL). The insoluble material was filtered off, the layers separated and the aqueous phase was added to the insoluble material and acidified with 10% hydrochloric acid solution. The separated crystalline product was collected, washed with water and the solid was crystallized from a large volume of methanol to provide 7.85 g (61.5%) of the yellow crystalline 5-bromo-2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid; mp 159-161° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.I([O-])(=O)(=O)=[O:38].[Na+]>CO.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][S:34](=[O:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCSCC4)c3)cc2n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCS(=O)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) and sodium periodate (43 mg, 0.2 mmol) in MeOH/water (3:1, 4 mL) was stirred overnight at rt. The reaction was partitioned between EtOAc and brine and the organic phase dried, filtered and concentrated in vacuo to give 1-oxo-thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (30 mg, 58%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.37 (1H, s), 8.25 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.96 (1H, t), 7.82 (1H, s), 7.71-7.74 (1H, m), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.96-6.98 (1H, m), 6.67 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 3.99-4.04 (2H, m), 3.66-3.74 (2H, m), 2.84-2.93 (2H, m), 2.65-2.70 (2H, m); m/z (LC-ES+) 518 [M+H]+.
Reaction SMILES: [ClH:1].CC([CH:6]1[CH2:11][N:10](C([O-])=O)[CH2:9][CH2:8][N:7]1[C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])(C)C>C(O)(C)C.ClCCl>[ClH:1].[N:7]1([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:8][CH2:9][NH:10][CH2:11][CH2:6]1
Reactant: CNC(=O)COC(=O)N1CCN(C(=O)[O-])CC1C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)COC(=O)N1CCNCC1
Reaction time: 1 h

Procedure:
25 ml of a 6N solution of hydrogen chloride in isopropanol are added to a solution of 2.68 g (8.9 mmol) of 2-(methylamino)-2-oxoethyl 1,1-dimethylethyl-1,4-piperazinedicarboxylate, obtained according to step 5.1, in 25 ml of dichloromethane. Stirring is continued at room temperature for 1 hour. The organic phase is removed by filtration through a hydrophobic cartridge and the acidic aqueous phase is concentrated under reduced pressure. After crystallization from isopropanol, 2.05 g of product are obtained in the form of a white solid, and are used without further purification in the following step.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].[CH3:6][C@H:7]1[O:12][C@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[C:4]([CH2:3][CH2:2][N:9]1[CH2:10][C@@H:11]([CH3:13])[O:12][C@H:7]([CH3:6])[CH2:8]1)#[N:5]
Reactant: N#CCCBr
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H]1CN(CCC#N)C[C@@H](C)O1
Temperature: 20 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
3-Bromopropionitrile (4.06 g, 0.03 mole), cis/trans-2,6-dimethylmorpholine (4.0 g, 0.034 mole), triethylamine (5.0 ml ) and ethanol (50 ml ) were refluxed (78° C.) for 3 hours and left stirring at 20° C. for 17 hours. The solvent was evaporated and the residue purified by chromatography using silica gel/chloroform: 5% methanol to give els/trans N-(2-cyanoethyl)-2,6-dimethylmorpholine (4.0 g, 79%) as a colourless oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]([NH:9][C@H:10]1[CH2:27][C:26]2=[CH:28][N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:29])=[O:8])(=O)C.[NH4+].[OH-]>CO>[SH:4][CH2:5][CH:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]([NH:9][C@H:10]1[CH2:27][C:26]2=[CH:28][N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:29])=[O:8]
Reactant: CC(=O)SCC(CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(CS)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the less polar stereoisomer of (10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide (50 mg, 0.106 mmol) in 10 mL of methanol at 0° C. under argon was added 0.5 mL concentrated NH4OH. The reaction mixture was stirred from 0° C. (ice-bath was removed after addition of NH4OH) to room temperature and further stored at room temperature for 1 hour. Excess methanol was removed under reduced pressure to give a white solid residue. The residue was partitioned between ethyl acetate (30 mL) and 0.1 NHCl (15 mL). The organic layer was washed with brine (15 mL), dried (MgSO4), and evaporated to dryness. The solid residue was stirred in 50% ether/pet. ether and filtered to yield the more polar stereoisomer of (10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as a white powder, 41 mg (90%) m.p. 224° C.