Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
6-Amino-9-benzyl-2-(isopropylamino)purine (71 mg, 0.25 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (73 mg, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: COCCl
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cccc(Cl)c1Cl
Yield: 100.5 %

Procedure:
A mixed solution of 2,3-dichlorophenol (16.3 g, 0.10 mol), chloromethyl methyl ether (9.7 g, 0.12 mol), anhydrous potassium carbonate (27.6 g, 0.20 mol), and acetonitrile (150 ml) is stirred at a temperature between 50° C. and 60° C. for 40 minutes and evaporated under reduced pressure to remove acetonitrile. The residue is dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 20.8 g (Yield 100%) of 2,3-dichlorophenyl methoxymethyl ether as a pale yellow oil. To a hexane solution (35 ml) of 8.12 g (0.07 mol) of N,N,N',N'-tetramethylethylenediamine is dropwise added 50 ml of 15% hexane solution of butyl lithium while being stirred at a temperature of -10° C. to 0° C. and the mixture is stirred for 15 minutes.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: NC(=O)Cc1nc(Cl)nc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2nc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 50 °C

Procedure:
2-(2-chloro-quinazolin-4-yl)-acetamide (221 mg, 1.0 mmol) is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and N-methylpiperazine (555 μL, 5.0 eq.) is added. The mixture is heated 45 min. at 50° C. AcOEt is added and the suspension is filtered to afford 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:17](Cl)(Cl)=[O:18]>>[F:16][C:3]1[C:2]([N:1]=[C:17]=[O:18])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C(Cl)Cl
Product: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21

Procedure:
6-Amino-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine which is used as the starting material in Example 2. 1H-NMR (CDCl3, 60 MHz): 7.02 ppm (d, 1H), 6.88 ppm (d, 1H), 4.88-4.60 ppm (m, 4H), 2.35 ppm (t, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]1[O:9][CH2:8]1>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:8][CH:7]([OH:9])[CH2:6][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NCCCO
Reactant: CCCCCCCCCCCCCCOCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(O)CNCCCO
Temperature: 80 °C
Yield: 135 %

Procedure:
A 300-ml two-necked flask equipped with a stirrer and a dropping funnel was charged with 25.1 g (0.33 mol) of 3-amino-1-propanol and 6.00 g of ethanol, and the contents were heated and stirred at 80° C. in a nitrogen atmosphere. After 9.00 g (33 mmol) of tetradecyl glycidyl ether were added dropwise over 2 hours, the resultant mixture was stirred further for 1 hour. The reaction mixture was poured into 400 ml of ice water and stirred for 1 hour. Crystals formed were then collected by filtration and recrystallized from methanol, thereby obtaining 15.4 g (yield: 92%) of the title compound (IIa-5).
Reaction SMILES: [H-].[Na+].C1([C@H]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])C)C=CC=CC=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[CH2:21]([N:13]1[CH:14]2[C:18](=[O:19])[O:17][CH2:16][CH:15]2[NH:11][C:12]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1OCC2NC(=O)N(Cc3ccccc3)C12
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]-imidazol-2,4(3H,3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of water. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS,6aR)-1-[R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent). Concerning the product:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].C(C1C(=O)C([Cl:25])=C(Cl)C(=O)C=1C#N)#N.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:25][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Temperature: 90 °C
Yield: 50 %

Procedure:
6-Nitro-3,4-dihydro-1H-quinolin-2-one (12.56 g, 65.4 mmol) was suspended in toluene (200 mL), to which DDQ (15.06 g, 66.3 mmol) was added. Phosphoryl trichloride (30.5 mL, 327 mmol) was then added dropwise and the reaction mixture was then heated at 90° C. for 3 hours. It was then observed that the deep red semi-solution had become an orange free flowing suspension, which LC-MS confirmed contained desired product. The reaction mixture was then poured slowly into ice water (1 L), keeping temperature below 10° C. This solution was then neutralized to pH 7 via slow addition of 2.5M aq. sodium hydroxide, keeping temperature below 10° C. This brown suspension was then extracted with ethyl acetate. The aqueous layer was back extracted further with ethyl acetate, and the combined organic layers were washed with brine. The resulting orange/brown solution was dried over MgSO4, filtered and concentrated to afford a brown/orange solid, which was dried under high vacuum overnight. The mass of dry material (2-chloro-6-nitro-quinoline) was 7.2 g (50% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:23]3[C:30]4[CH2:31][CH2:32][CH:33]([CH2:35][CH2:36][OH:37])[CH2:34][C:29]=4[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:23]3[C:30]4[CH2:31][CH2:32][CH:33]([CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34][C:29]=4[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Methanesulfonyl chloride (0.48 mL, 707 mg, 6.17 mmol, 1.2 equiv.) was added to a suspension of 2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol (2.4 g, 5.14 mmol, 1 equiv.) in anhydrous DCM (20 mL) at 0° C. The resulting mixture was stirred overnight during which time it was warmed to ambient temperature. The standard aqueous work-up gave Methanesulfonic acid 2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethyl ester as a slight yellow solid (2.3 g, 79%). 1H-NMR (CD3OD) δ 8.56 (s, 1H), 8.33 (s, 1H), 7.85 (t, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.51 (dd, J=2.5, 9.1 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8.8 Hz, 1H), 5.27 (s, 2H), 4.35 (t, 2H), 3.19 (s, 3H), 3.15 (m, 3H), 2.97 (m, 1H), 2.17 (m, 2H), 1.81 (m, 2H), 1.54 (m, 1H).; LCMS RT=3.03 min; [M+H]+=545.
Reaction SMILES: [C:1](O)(=O)C.[F:5][C:6]([F:50])([F:49])[C:7]1[CH:8]=[C:9]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:10][N:11]([C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:20]2[C:32]([CH3:41])=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:19]1=2)[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1.C=O.C([BH3-])#N.[Na+]>C(#N)C.ClCCl>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[C:9]([CH:8]=[C:7]([C:6]([F:5])([F:49])[F:50])[CH:44]=1)[CH2:10][N:11]([C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH3:1])[CH2:30][CH2:31]2)[C:20]2[C:32]([CH3:41])=[C:33]([C:37]([F:38])([F:39])[F:40])[C:34]([CH3:36])=[CH:35][C:19]1=2)[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1
Reactant: CC(=O)O
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCN(C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 18 h

Procedure:
Add glacial acetic acid (0.25 mL) over 25 minutes to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 160) (0.038 g, 0.057 mmol), 37% aqueous formaldehyde (0.014 mL, 0.189 mmol) and sodium cyanoborohydride (0.011 g, 0.172 mmol) in acetonitrile (2.5 mL) at room temperature under an atmosphere of nitrogen and stir for 18 h. Dilute the reaction with dichloromethane (20 mL) and wash with 2 N sodium hydroxide and brine (10 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with dichloromethane/methanol/concentrated ammonium hydroxide (90:10:1), to provide the title compound as a white crushable foam (0.028 g, 72%). 1H NMR (CDCl3, 500 MHz) δ 1.15-1.70 (m, 4H), 1.83-2.06 (m, 7H), 2.33-2.35 (m, 9H), 2.76-3.03 (m, 5H), 3.24 (br s, 1H), 4.13 (m, 3H), 4.80-4.87 (m, 1H), 5.14 (br s, 1H), 5.58 (br s, 1H), 6.58 (m, 1H), 7.77-7.78 (m, 3H); ESI MS m/z 678 [C31H36F9N7+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 74.1 %

Procedure:
A solution of 2.30 g (5.77 mmol) of (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionic acid, 0.60 ml (0.62 g, 5.77 mmol) of benzyl alcohol, 0.07 g (0.58 mmol) of 4-dimethylaminopyridine and 1.33 g (6.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in 30 ml of dichloromethane was stirred at RT overnight. The reaction mixture was washed successively with 1N hydrochloric acid, 1N sodium bicarbonate solution and with water. After drying over sodium sulfate, filtering and concentrating, the residue was chromatographed on silica gel. 2.09 g of the title compound were obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][CH:13]([Cl:18])[C:14]([CH2:16]Cl)=O>C(COC)OC>[Cl:12][CH:13]([Cl:18])[C:14]1[N:9]=[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]2[CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(CCl)C(Cl)Cl
Solvent: COCCOC
Product: FC(F)(F)c1ccc2nc(C(Cl)Cl)cn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(Trifluoromethyl)pyridin-2-amine (12.9 g) was dissolved in dimethoxyethane (150 mL) was added 1,1,3-trichloroacetone (12.7 mL) at room temperature, and the mixture was stirred overnight. The precipitated solid was collected, and suspended in ethanol (50 mL), and the mixture was heated under reflux for 3 hr. After allowing to cool to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give 2-(dichloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (10.3 g) as a white solid. The obtained solid was suspended in a mixed solvent of water (100 mL) and tetrahydrofuran (20 mL), and calcium carbonate (8.0 g) was added to the mixture at room temperature, and the mixture was stirred at 100° C. for 1 hr. The mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. The residue was washed with diisopropyl ether to give the title object compound (7.3 g, 43%) as white crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CN2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(morpholin-4-ylmethyl)benzonitrile (Description 122, 0.5 g, 2.5 mmol) in THF (7 mL) at 0° C. was added dropwise a solution of LiAlH4 (1.0 M in THF, 2.5 ml, 2.5 mmol). The reaction was stirred at 0° C. for 1 h. Additional LiAlH4 (1.0 M in THF, 1.0 ml, 1.0 mmol) was added and the reaction stirred for an additional 30 min. The reaction was quenched by the addition of water (0.13 mL) followed by 15% NaOH solution (0.13 ml) and stirred vigorously for 1 h. The reaction was filtered through celite, evaporated and azeotroped twice with toluene. The amine was used crude.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of N-t-butoxycarbonyl-2-hydroxy-5-chlorobenzylamine (730 mg, 2.83 mmol), Cs2CO3 (923 mg, 2.83 mmol) and ethylbromoacetate (0.314 ml, 2.83 mmol) on DMF (5 ml) was stirred for 2 h. The crude reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil which was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]=[C:13]=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CCN=C=O)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
4.53 g (30 mol) of 4-methoxy-β-phenylethylamine are added dropwise to a solution of 2.96 g (10.0 mol) of triphosgene in 30 ml of dry tetrahydrofuran and the mixture is heated at the boiling point for 2 hours. The solution is cooled to room temperature and filtered and the filtrate is concentrated in vacuo. The colorless oil which remains is purified by bulb tube distillation under a pressure of 2 mmHg at a bath temperature of 220° C. to give 1.1 g of 4-methoxy-β-phenylethyl isocyanate. 0.7 g (4.0 mmol) of 4-methoxy-β-phenylethyl isocyanate and 0.4 g (3.5 mmol) of 3-ethyl-4-methyl-2-oxo-3-pyrroline are stirred with one another and the mixture is heated at 150° C. for one hour. The cooled reaction mixture is dissolved in a minimum of ethyl acetate and purified by column chromatography over silica gel 60 with the aid of the mobile phase ethyl acetate (Rf =0.5). After the eluent has been evaporated off under reduced pressure, 0.25 g of methoxy-4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido)-ethyl]-benzene is obtained, and is introduced in portions into chlorosulfonic acid cooled to 0° C. After being stirred at 0° C. for one hour, this reaction mixture is poured onto ice. The sulfonic acid chloride which has precipitated is taken up in ethyl acetate. The organic phase is dried with sodium sulfate and concentrated in vacuo to give the sulfonic acid chloride as a crude product, which is dissolved in acetone and converted into 2-methoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido)-ethyl]-benzenesulfonamide with aqueous ammonia solution. The sulfonamide has a melting point of 204°-205° C.
Reaction SMILES: [F:1][C:2]1([CH2:18][CH2:19][N:20]2[C:24](=[O:25])[CH2:23][O:22][C:21]2=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH3:27][NH2:28]>O1CCCC1>[F:1][C:2]1([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH2:3][CH2:4][N:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:7]1
Reactant: O=C1COC(=O)N1CCC1(F)CCN(c2ccc3ccccc3n2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1(F)CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.52 g (1.46 mmol) of 3-{2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 12.8, and 3.6 ml (7.28 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 99/1 mixture of ethyl acetate and methanol, followed by crystallization from diethyl ether, 0.390 g of pure product is obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:17]=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]=2[CH:17]=[O:18])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3cccnc3n2-c2ccccc2)CC1
Temperature: 110 °C
Yield: 99.4 %

Procedure:
A solution of 2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (210 mg, 0.818 mmol) in 1,4-dioxane (10 mL) is treated with [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.80 mL, 4.11 mmol) and the resulting yellow solution is heated to 110° C. under a reflux condenser for 19.5 hours. The reaction mixture is evaporated to give an orange oil. The residue is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane, increasing to dichloromethane:methanol (99:1). Fractions containing the product are combined and the solvent evaporated to give 342 mg of 4-(3-formyl-1-phenyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a yellow orange glass (99.5% yield). MS: m/e 421 (M+H), 443 (M+Na), 365 (M-C4H8+H), 343(M-C5H8O2+Na), 321(M-C5H8O2+H). 1H NMR (300 MHz, CDCl3): 10.23 (1H, s), 8.49 (1H, d), 8.22 (1H, dd), 7.64-7.48 (3H, m), 7.42 (2H, d), 7.19 (1H, dd), 3.50-3.29 (8H, m), 1.65-1.52 (2H, m), 1.44 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:12]([CH2:25][CH3:26])[S:11][C:10]2=[O:27])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:12]([CH2:25][CH3:26])[S:11][C:10]2=[O:27])=[CH:28][CH:29]=1
Reactant: CCC1SC(=O)N(Cc2ccc([N+](=O)[O-])cc2)N=C1c1ccc(OC)c(OC)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCC1SC(=O)N(Cc2ccc(N)cc2)N=C1c1ccc(OC)c(OC)c1

Procedure:
A solution of 3.9 g of 3-(4-nitrobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one in 40 ml of tetrahydrofuran is hydrogenated in the presence of Raney nickel. The catalyst is filtered off and the solution is concentrated. Recrystallization gives 3-(4-aminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 105°.