Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>CCOCC.O>[ClH:29].[CH3:21][O:20][CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:15]=1
Reactant: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (12 mg, 0.03 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 301 (M−Cl).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([Cl:15])=[CH:10][CH:11]=2)[C:6]1=NN(C)C.[O-:22]I(=O)(=O)=O.[Na+].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([Cl:15])=[CH:10][CH:11]=2)[C:6]1=[O:22]
Reactant: COC(CC1CCc2ccc(Cl)cc2C1=NN(C)C)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(CC1CCc2ccc(Cl)cc2C1=O)OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 34.7 %

Procedure:
7-Chloro-1-(dimethylhydrazono)-1,2,3,4-tetrahydro-2-naphthaleneacetaldehyde dimethyl acetal (16.0 g) was dissolved under argon in 700 ml of tetrahydrofuran and 180 ml of water. The solution was treated in succession with 30.8 g of sodium (meta)periodate, 11.8 g of sodium acetate and 120 ml of acetic acid and stirred at 50° C. for 18 hours. Subsequently, 2000 ml of water were added and the mixture was extracted three times with 500 ml of ethyl acetate each time. The organic phases were washed with 500 ml of a saturated sodium chloride solution, combined, dried over MgSO4 and freed from solvent. The crude product, 18.4 g of dark brown oil, was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:3) as the eluent. There were obtained 4.8 g (35%) of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[Si:46]([O:63][CH2:64][C:65]1[C:66]([NH2:71])=[N:67][CH:68]=[CH:69][CH:70]=1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[Si:46]([O:63][CH2:64][C:65]1[C:66]([NH:71][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:26])=[N:67][CH:68]=[CH:69][CH:70]=1)([C:59]([CH3:60])([CH3:61])[CH3:62])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(C)[Si](OCc1cccnc1N)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3ncccc3CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (303 mg, 0.848 mmol) in DMF (5 mL) was added triethylamine (103 mg, 1.02 mmol), followed by dropwise addition of 2,4,6-trichlorobenzoyl chloride (227 mg, 0.933 mmol). The reaction was stirred for two hours. 3-((tert-Butyldiphenylsilyloxy)methyl)pyridin-2-amine (369 mg, 1.02 mmol) was added and the reaction mixture was heated to 60° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to give (R)-N-(3-((tert-butyldiphenylsilyloxy)methyl)pyridin-2-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added THF (5 mL) and TBAF (848 μL, 0.848 mmol). The reaction mixture was stirred for one hour, then quenched with saturated NH4Cl (1 mL) and then concentrated under reduced pressure to give crude (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-(hydroxymethyl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added HCl (4M in dioxane, 5 mL). The reaction mixture was sealed and heated to 100° C. for four hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and the organic layer was washed with saturated NaHCO3 (5 mL), water (5 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure to give crude (R)-N-(3-(chloromethyl)pyridin-2-yl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added DMF (10 mL) and Cs2CO3 (276 mg, 0.848 mmol). The reaction mixture was heated to 60° C. for 4 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to afford the title compound (8.0 mg, 2.2% yield). MS (apci) m/z=432.3 (M+H).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=4)[N:19]([CH3:29])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)CCC>>[CH3:29][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:17]([C:16]2[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(I)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(-c3cccs3)cc21
Yield: 37.3 %

Procedure:
3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophen-2-yl-1H-indol-3yl)-pyrrole-2,5-dione (180 mg, 37%) was prepared from 3-(6-iodo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (525 mg, 1 mmol) and 2-(tributylstannyl)thiophene (0.98 mL, 3.09 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(OCC)C.[Mg].[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[N:19]>C1(C)C=CC=C(C)C=1>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:18](=[NH:19])[C:17]([CH3:21])([CH3:20])[CH3:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)C#N
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1cccc(C)c1
Product: CC(C)(C)C(=N)Cc1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzyl bromide (0.1 mol) and dry diethyl ether (200 mL) are placed in a flame-dried, 2-necked round bottomed flask at RT. The solution is stirred under an inert atmosphere while magnesium turnings (0.1 mol) are added portionwise. Trimethylacetonitrile (0.1 mol) is then added, followed by dry m-xylene (100 mL). The reaction is stirred at RT for 1 h and then the diethyl ether is distilled off (oil bath temp. 130° C.). A further portion of trimethylacetonitrile (5 mL) is added and the resulting suspension is heated at reflux overnight under an atmosphere of dry nitrogen. The reaction mixture is cooled to 0° C. and a solution of concentrated hydrochloric acid (22 mL) in water (40 mL) is added slowly. The resulting solid is filtered off and dried under vacuum to give 1-(4-chlorobenzyl)-2,2-dimethyl-propylideneamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[C:27]([Mg]Br)[CH:26]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5]([C:27]2[CH:26]=[C:25]([CH3:33])[CH:30]=[CH:29][CH:28]=2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)c2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-nitrobenzoic acid (2.5 g, 12.40 mmol) in tetrahydrofuran (50 mL) was treated with oxalyl chloride (1.194 mL, 13.64 mmol) followed by DMF (0.096 mL, 1.240 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling to 0° C., a 1M solution of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hr another portion of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hour, the reaction mixture was partitioned between ethyl acetate (200 mL) and 1N HCl (150 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=ethyl acetate/heptane, REDISEP® SiO2 120 g) to provided Intermediate A-18A (0.700 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.71 (dd, J=7.7, 1.1 Hz, 1H), 7.66-7.54 (m, 3H), 7.52-7.46 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].N1CCOCC1.Cl>CS(C)=O>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][C:1]([CH:4]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]2=[O:10])=[O:3])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: COc1cc(C=CC(=O)C2C(=O)CCC2=O)ccc1O

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.03 g.) was treated with 4-hydroxy-3-methoxybenzaldehyde (5.05 g.) in 50 ml. of dimethylsulfoxide at 80° C for 13 minutes in the presence of 4 ml. of morpholine. After cooling, 80 ml. of 1 N hydrochloric acid was added to the reaction mixture, depositing a crystalline product. The solid was collected by filtration, and washed with water and ethanol successively, and it was then dried. The Claiseu-Schmidt condensation product, 2-(4-hydroxy-3-methoxycinnamoyl)-1,3-cyclopentanedione, (1.3 g.) was obtained in an orange crystalline form, which showed mp. 274°- 275° C after recrystallization from dioxane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=3)[CH2:12][CH2:13]2)[CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 257) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 523.3 (MH+).
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([N:11]([CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[NH:32])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C:38](=[NH:43])(OCC)[CH3:39].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:38]([N:22]1[CH2:21][CH2:20][CH:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([N:11]([CH2:25]/[CH:26]=[CH:27]/[C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([NH2:33])=[NH:32])[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:17][CH:16]=2)[CH2:24][CH2:23]1)(=[NH:43])[CH3:39]
Reactant: N=C(N)c1cccc(/C=C/CN(Cc2ccccc2)c2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 210 %

Procedure:
To a solution of 3-[3-[N-benzyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (335 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (230 mg) and triethylamine (0.51 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 30% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (252 mg, yield 70%) as a colorless amorphous solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:10][CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH:7]=1)[CH3:11]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D46, 276 mg, 1.39 mmol) in dimethylformamide (10 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (278 mg, 1.39 mmol) and diisopropylethylamine (0.241 ml, 1.39 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with a mixture of ethyl acetate/diethyl ether (×2). The combined extract was dried and concentrated under vacuum to afford the title compound as a yellow oil/solid (514 mg, 97%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34][CH3:35])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[O:18][CH2:17][C@H:16]([CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([O:40][C:41]([N:43]([CH3:49])[CH2:44][CH2:45][C:46]([OH:48])=O)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]([CH3:49])[CH2:44][CH2:45][C:46]([N:30]([CH3:31])[CH2:29][CH2:28][C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:32]([O:34][CH3:35])=[O:33])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[O:18][CH2:17]1)=[O:48])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: CNCC[C@H]1COc2c(OC)cccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](CCN(C)C(=O)CCN(C)C(=O)OC(C)(C)C)COc1c(OC)cccc1-3

Procedure:
The title compound was prepared in analogy to Example 13, Step 6 from methyl (7R)-14-cyclohexyl-4-methoxy-7-[2-(methylamino)ethyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate and N-(tert-butoxycarbonyl)-N-methyl-β-alanine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([CH3:36])[NH:26][C:25]=1[CH:37]=O>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:25]1[NH:26][C:27]([CH3:36])=[C:28]([CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCOCC1

Procedure:
5-(2,6-Dichlorophenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 3,5-dimethyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde to give 2.0 g of the titled compound as an orange solid.
Reaction SMILES: O([C:8]1[C:20]2[N:19]3[C:14]([CH2:15][O:16][CH2:17][CH2:18]3)=[CH:13][C:12]=2[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[C:24]([Cl:37])[CH:23]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>C(OCC)(=O)C>[ClH:37].[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:8]2[C:20]3[N:19]4[C:14]([CH2:15][O:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH:36]=[CH:35][C:25]=1[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]
Reactant: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Reactant: c1ccc(Oc2ncnc3cc4n(c23)CCOC4)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(Oc2ccc(Nc3ncnc4cc5n(c34)CCOC5)cc2Cl)c1
Temperature: 140 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
A mixture of 4-phenoxy-6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazine (69 mg), 3-(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridine hydrochloride (75 mg) and 1-methyl-2-pyrrolidone (1 mL) was stirred at 140° C. for 14 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=50/50→0/100). The obtained fractions were collected and concentrated, and the residue was dissolved in ethyl acetate (2 mL) and treated with 4N hydrochloric acid/ethyl acetate (0.13 mL) to give the title compound (81 mg) as hydrochloride crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C[Si]([C:19]#[N:20])(C)C>C(O)(=O)C>[C:2]1([NH:1][C:8]2([C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCCCC1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
1.4 ml (15.3 mmol) of aniline are added to a solution of 1.3 ml (12.5 mmol) of cyclohexanone in 20 ml of acetic acid at 0° C. The solution is stirred for 10 minutes and 1.9 ml (14.2 mmol) of trimethylsilyl cyanide are added. The reaction medium is stirred overnight at room temperature. It is then gently poured into a solution of ice-cold ammonium hydroxide, while keeping the pH basic, and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The residue is precipitated in dichloromethane and heptane. The solid is filtered and dried. 2.2 g of 1-phenylaminocyclohexanecarbonitrile are obtained in the form of whitish crystals. Yield=88%, m.p.=67-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][O:26][C@:18]2([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:17])[C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@H]2CS1
Yield: 149.4 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(3-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol) and TFA (18.85 μL, 0.245 mmol) in DCM (122 μL) was stirred at rt for 3 h, and the solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-3-fluoropicolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, METHANOL-d4) δ 8.84-8.37 (br. s, 2H), 8.17 (dd, J=7.2, 2.3 Hz, 1H), 7.92-7.76 (m, 2H), 7.26 (dd, J=11.1, 8.9 Hz, 1H), 4.37-4.19 (m, 2H), 3.46 (dd, J=13.6, 3.8 Hz, 1H), 3.35-3.25 (m, 1H), 3.19-3.04 (m, 1H), 2.32 (q, J=7.0 Hz, 2H). MS (M+H)+: 391.10.
Reaction SMILES: [F:1][C:2]([F:15])([CH:13]=C)[C:3]([CH2:11][CH3:12])([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:4][CH3:5].[O:16]=[O+][O-]>ClCCl.O=O>[F:1][C:2]([F:15])([C:3]([CH2:11][CH3:12])([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:4][CH3:5])[CH:13]=[O:16]
Reactant: O=[O+][O-]
Reactant: C=CC(F)(F)C(CC)(CC)O[Si](C)(C)C
Agent: O=O
Solvent: ClCCl
Product: CCC(CC)(O[Si](C)(C)C)C(F)(F)C=O
Temperature: -78 °C

Procedure:
4,4-difluoro-3-ethyl-3-trimethylsilyloxy-5-hexene (2.00 g, 8.88 mmol) was dissolved in dichloromethane (80 ml), and the solution was cooled to -78° C. A gaseous mixture of O3 in O2 was passed into the solution until it became blue. Nitrogen was bubbled through the solution to remove excess ozone, dimethyl sulfide (3 ml) was added, and the solution was brought slowly to room temperature. Following ozonide decomposition, dichloromethane was added, and the organic layer was washed with water (twice), dried over CaCl2 and concentrated under reduced pressure. Flash chromatography (50 g silica gel; 5% EtOAc in petroleum ether as eluant) to give the title compound as a pale yellow oil, δ 0.14 (s 9H), 0.91 (m, 6H), 1.64 (m, 2H), 1.85 (m, 2H), 9.55 (t, 1H).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=[O:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8 g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 1H NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH+); [α]D+28.8 (c 1.0, MeOH).