Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[BrH:15].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[NH2:9][C:7]1[S:8][C:4]([C:1](=[O:3])[CH2:2][Br:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(C)=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-acetyl-2-amino-4-thiazolecarboxylate (12.9 g) in a mixture of 30% solution of hydrogen bromide in acetic acid (50 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (21.1 g) at ambient temperature and stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (14.86 g). mp 164°-166° C. (dec.).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)=[O:13])[CH3:10]>C1COCC1.CO>[CH2:9]([O:11][C:12]([C:14]1[NH:15][C:16]([Br:8])=[CH:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(Br)[nH]1
Reaction time: 2 h
Yield: 55.3 %

Procedure:
NBS (0.15 mg, 0.83 mmol) was added to a stirred cold (0-5° C.) solution of 1H-pyrrole-2-carboxylic acid ethyl ester (200 mg, 1.44 mmol) in THF: MeOH (2:1, 24 mL). Stirring was continued at same temperature for 2 hrs. Solvent was removed under vacuum to get the residue. The residue obtained was purified by column chromatography (using silica gel of 200-430 mesh and 10% Ether in Hexane as eluent) to afford 100 mg (31.95% yield) of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 9.4 (bs, 1H), 6.8 (s, 1H), 6.2 (s, 1H), 4.4-4.2 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH2:33])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19].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>CN(C=O)C>[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH:33][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:17][CH:16]=3)[CH:12]=2)=[O:15])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cnn(Cc2ccc(CO)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carboxylic acid (220 mg, 0.95 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (238 mg, 0.95 mmol), HATU (7206 mg, 1.90 mmol) and DIPEA (0.64 mL, 2.84 mmol) in 5 mL DMF was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, dissolved in ethylacetate and extracted with aq. NaHCO3-solution. The organic layer was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). LCMS (method A) RtA=1.243 min; [M+H]+=466.0.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:8]=[CH:7][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: COCCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(Nc2cccc(Cl)c2)ncn1
Temperature: 200 °C
Yield: 70 %

Procedure:
75 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 30 mg of 2-methoxyethanamine and 88 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-(3-Chlorophenyl)-N6-(2-methoxyethyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:38])[C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])=[CH:19][CH:18]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])[CH3:3].COC1C(CCN)=CC(OC)=C([125I])C=1.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:38])[C:6]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])=[CH:21][CH:22]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([S:61]([C:58]2[CH:57]=[CH:56][C:55]([O:54][CH3:53])=[CH:60][CH:59]=2)(=[O:63])=[O:62])[CH2:14][CH2:15]1)=[O:7])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCNCC2)C(=O)C(=O)OCC)cc1
Agent: CN(C)c1ccncc1
Agent: COc1cc(CCN)c(OC)cc1[125I]
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.7 %

Procedure:
To a solution of ethyl[{4-[(dodecylamino)carbonyl]benzyl}(piperidin-4-ylmethyl)amino](oxo)acetate hydrochloride (900 mg, 1.63 mmol), DIAE (527 mg, 4.07 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous THF (50 mL) was added 4-methoxybenzene-sulfonyl chloride (404 mg, 1.96 mmol) dissolved in THF (2.0 mL). The reaction mixture was stirred 14 h at rt. The solvent was evaporated and the resulting residue was dissolved in DCM (100 mL), washed with water (20 mL) and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/1 in about 1 h) to give the title compound as a white foam (992 mg, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, 2H, J=8.3 Hz), 7.69 (d, 2H, J=9.2 Hz), 7.27 (t, 2H, J=7.9 Hz), 7.07 (m, 2H), 6.12 (m, 1H), 4.60 (s, 1H), 4.48 (s, 1H), 3.89 (s, 3H), 3.76 (m, 2H), 3.13 (d, 1H, J=6.8 Hz), 3.07 (d, 1H, J=7.0 Hz), 2.32-2.12 (m, 2H), 1.80-1.55 (m, 6H), 1.45-1.20 (m, 24H), 0.89 (t, 3H, J=7.9 Hz). M−(APCI): 684.4. HPLC (Condition A), Rt: 6.84 min (HPLC purity: 99.7%).
Reaction SMILES: [C:1](O)(=[S:3])[CH3:2].[O:5]1[C:16]2[C:8](=[CH:9][C:10](=[CH:14][CH:15]=2)[CH2:11]C=C)[O:7][CH2:6]1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.O>[O:5]1[C:16]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:2][CH2:1][SH:3])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: CC(O)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
25 g of thioacetic acid was added to 53.5 g of safrole in portions, while stirring the mixture at a room temperature or under cooling with ice/water. The reaction was carried out for 30 minutes. A solution of 20 g of sodium hydroxide in a mixture comprising 100 ml of water and 200 ml of ethanol was added to the reaction mixture. The obtained mixture was heated under reflux for 20 minutes, cooled, neutralized with dilute sulfuric acid and extracted with 1 l of benzene. The extract was washed with water and the benzene layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (hexane) to obtain 42.8 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]1[C:24]([SH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[S:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:18])[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: Cc1ccccc1S
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1Sc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), o-thiocresol (12.4 g), and 1N sodium bicarbonate (300 ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-5-sulphamyl-4-o-tolylthio-benzoic acid was filtered off and washed with 1N sodium bicarbonate solution. The sodium salt was dissolved in hot water (250 ml), and the acid was precipitated by the addition of 4N hydrochloric acid (17 ml). After isolation, recrystallization from aqueous ethanol, and drying at 115°C and 10 mm Hg for 3 hours, the acid was obtained with a melting point of 165°-166°C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Reactant: O=C1CCCC(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (2.0 g, 5.1 mmol) and THF (200 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (6.1 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then glutaric anhydride (0.69 g in 10 mL THF, 6.0 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product Compound 11 (670 mg, 26%) as a white solid. NMR (300 MHz, CD3OD) δ 7.75 (d, J=7.0 Hz, 2H), 7.68 (m, 1H), 7.50 (d, J=6.9 Hz, 2H), 7.15 (t, J=6.9 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 1.80 (t, J=6.8 Hz, 2H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[CH3:14]>CO>[CH3:14][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[CH3:12]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
To a cooled (6°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.74 g; 4.17 mmoles) in 80 ml of methanol was added dropwise over a period of 45 minutes a solution of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.96 g; 4.17 mmoles) [prepared in Step E] to give 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide, Rf=0.64 [Silica/CH2Cl2 :CH3OH (9:1)]. The temperature was maintained at 6° and anhydrous methylamine was bubbled into the solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 80 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and the residue was rechromatographed on 25 g of aluminum oxide using a gradient elution of methylene chloride-methanol to give 0.52 g of product. Recrystallization from isopropyl alcohol/ether yielded the title compound, mp 144°-148° (foaming).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Br:24]Br.C(OCC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:24][C:9]1[C:10]([C:21]([OH:23])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Yield: 81.2 %

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (20.0 g, 54.5 mmol) in dichloromethane (400 ml) was slowly added bromine (5.62 ml, 109 mmol) and the resulting mixture was reacted for 16 hours at room temperature. Diethyl ether (400 ml) and excess aqueous saturated NaHCO3 solution were successively added. The organic layer was separated, twice washed with aqueous saturated NaHCO3 solution and subsequently washed with brine, dried over MgSO4, filtered and concentrated to give 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (19.77 gram, 81% yield). Melting point: 222-224° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)[N:3]=1.C(N(CC)CC)C>[OH-].[OH-].[Pd+2].CN(C=O)C>[C:8]([C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])=[CH:5][C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20][CH2:19]2)=[N:3][CH:2]=1)#[N:9]
Reactant: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)nc(Cl)c1C#N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C#N
Temperature: 25 °C
Reaction time: 25.5 h
Yield: 97 %

Procedure:
A 300-mL Parr bottle charged with crude 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine (19.86 g, 52.29 mmol), 10.9 mL (7.94 g, 78.4 mmol, 1.50 equiv) of triethylamine, 220 mg Pd(OH)2 or 1.62 g (1.57 mmol, 3.0 mol %) of 20% palladium hydroxide on carbon [Pearlman's catalyst, 32.2% LOD] and 100 mL of dry DMF. The mixture was stirred at 25° C. and 48.9–43.2 psi of H2 for 25.5 hours. The pressure was vented, and the mixture was filtered through a 5.0 g pad of cellulose. The cellulose pad was washed with 10 mL of DMF. Water (400 mL) was added to the filtrate and the resulting mixture was stirred for 30 minutes. The precipitate was filtered, washed several times with H2O, and dried to afford 17.52 g (97.0%) of 5-cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thiomorphlin-4-yl)pyridine as a slightly grey solid (97% conversion).
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>O>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][Cl:25])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(C2CCCCCC2)cc1
Solvent: O
Solvent: c1ccncc1
Product: ClCCc1ccc(C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73.6 g of β-(p-cycloheptyl-phenyl)-ethanol are mixed with 31.6 ml of absolute pyridine. 29.5 ml of thionyl chloride are added dropwise to this mixture, whilst cooling with ice. Thereafter, the reaction mixture is slowly heated to 100°-110°C and kept at this temperature for 2 hours. The reaction solution is again cooled to room temperature, 69 ml of water are added, and the whole is extracted with a mixture of ether and chloroform. The organic phase is washed twice with 2 N sodium carbonate solution, three times with 2 N hydrochloric acid and finally once with 2 N sodium carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue, a brown oil, is distilled in a high vacuum. Hereupon, β-(p-cycloheptyl-phenyl)-ethyl chloride is obtained as a light yellow oil of boiling point 130°-5°C/0.2 mm Hg.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.Cl.ClCCN1CCCC1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 1.96 g, 45 mmol) was added portionwise at room temperature to a solution of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (6.01 g, 30.0 mmol) in N,N-dimethylacetamide (150 ml), then a solution of 1-(2-chloroethyl)-pyrrolidine in toluene [prepared from commercially available 1-(2-chloroethyl)-pyrrolidine hydrochloride (16.1 g, 94.5 mmol) by partitioning between toluene (70 ml) and 1 M aq. sodium hydroxide solution (70 ml) and drying of the organic layer with Na2SO4] was added dropwise. The reaction mixture was stirred at room temperature for 16 h, then heated at 75° C. for 80 min. After cooling, the reaction mixture was partitioned between diethyl ether and sat. aq. sodium hydrogen-carbonate solution. The organic layer was dried (Na2SO4) and evaporated. Crystallization of the residue from diethyl ether afforded the title compound (3.74 g, 42%). White solid, MS (ISP)=298.2 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: COC(=O)c1ccc2c(SC)c[nH]c2c1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Temperature: 120 °C

Procedure:
Potassium tert-butylate (4.41 g, 39.36 mmol) and 5-bromo-2-chloro-pyrimidine (5.0 g, 26.2 mmol) were added to a solution of methyl 3-(methylthio)-1H-indole-6-carboxylate (5.8 g, 26.2 mmol) in DMF (60 mL). The resulting mixture was heated at 120° C. for 16 h, then cooled and poured onto ice-cold water (100 mL). The mixture was extracted with MTBE (3×50 mL) and the combined organic layers were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography [100-200 mesh silica; ethyl acetate/hexane=1:9]. White solid. Yield: 6.0 g (61% of theory). HPLC-MS (method 5): Rt=4.15 min; m/z [M+H]+=379
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COCOCC#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCOCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.66 g of 4-methoxymethoxy-but-2-ynoic acid and 0.60 mL of isobutyl chloroformate in 16 mL of tetrahydrofuran at 0° C. was added 0.5 mL of N-methylmorpholine followed by 1.2 g of solid N-(3-bromophenyl)-4,6-quinazolindiamine. Stirring was continued for 1 hr at 0° C. and 30 min at room temperature. Another equal amount of mixed anhydride as prepared above was added. The mixture was stirred an addition 30 min and stored at −10° C. over night. The mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate and choroform solvent mixtures to give 0.35 g of 4-Methoxymethoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a tan solid: mass spectrum (m/e): M+H 441.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][OH:20])=[O:12])=[C:4]([F:21])[CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:12])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(NC(=O)N2CCCCC2CO)c(F)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)N2CCCCC2COC(=O)C(C)(C)C)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
15.9 g (0.05 mol) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-hydroxymethylpiperidine (Example 1) and 4.7 g (0.06 mol) of pyridine are dissolved in 200 ml of toluene, and 6.0 g (0.05mol) of pivaloyl chloride are added dropwise at 20° C. The mixture is stirred for 3 hours at 50° C. and washed with twice 100 ml of water, and the toluene phase is dried over sodium sulfate. After the solvent as been removed, 18.4 g (92% of theory) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-pivaloyloxymethylpiperidine are obtained in the form of a colorless viscous oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:34]1[C:43]2[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1>C(O)(C)C>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[CH:36][CH:35]=[C:34]2[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: COc1cccc2c(Cl)ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCN(CCN1CCN(c2ccnc3c(OC)cccc23)CC1)C1CCc2ccc(O)cc2C1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of 9a (0.6 g, 1.89 mmol) and diisopropylethylamine (0.4 mL, 2.08 mmol, 1.1 equiv) in 15 mL isopropanol was added 4-chloro-8-methoxyquinoline (17) (0.366 g, 1.89 mmol, 1 equiv). The mixture was refluxed with stirring for overnight. It was then evaporated and concentrate was dissolved in CH2Cl2 (50 mL) and the solution obtained was washed with 5% NaHCO3 (3×50 mL), brine (2×50 mL), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was purified through column chromatography using 20% methanol in ethyl acetate to give 18a as white wax (0.66 g, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-0.95 (t, 3H, 4 Hz), 1.75 (m, 3H), 2.11-2.21 (m, 2H), 2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47 (s, 1H), 4.02 (s, 3H), 6.60 (s, 1H), 6.66-6.68 (d, 1H, J=8 Hz), 6.82-6.84 (t, 2H, J=4 Hz), 6.98-7.00 (d, 1H, J=8 Hz), 7.36-7.42 (t, 1H, J=12 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 8.67-8.68 (d, 1H, J=4 Hz).