Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Yield: 88.9 %

Procedure:
A mixture 25.0 g (0.16 mole) of 3-fluoro-4-nitrophenol, 27.6 g (0.20 mole) of potassium carbonate, and 28.4 g (0.20 mole) of methyl iodide in 2-butanone was heated at 70° C. for approximately 17 hours. The reaction mixture was then poured over ice and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving 24.35 g of 3-fluoro-4-nitroanisole as a solid residue. The NMR spectrum was consistent with the proposed structure. This product was used in Step B without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[N:12][N:13]=[CH:14]3)O1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]3)[CH:35]=2)=[C:25]2[CH:29]=[C:28](Cl)[O:27][C:26]=12>>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:37][CH2:38][N:39]([C:42](=[O:44])[CH3:43])[CH2:40][CH2:41]3)[CH:35]=2)=[C:25]2[CH:29]=[C:28]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[N:12][N:13]=[CH:14]4)[O:27][C:26]=12
Reactant: CC1(C)OB(c2cccc3cnncc23)OC1(C)C
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnncc56)cc34)cn2)CC1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazine and 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone, by a procedure analogous to Example 223, Step D. The sample underwent both mass-directed purification and preparative TLC during purification. 1H NMR (400 MHz, CD3OD): δ 10.32 (s, 1H), 9.73 (s, 1H), 8.63 (dd, J=0.76, 7.58 Hz, 1H), 8.32 (d, J=8.08 Hz, 1H), 8.18-8.25 (m, 2H), 7.96-8.03 (m, 2H), 7.76 (s, 1H), 4.67-4.76 (m, 1H), 4.55-4.61 (m, 1H), 3.35-3.42 (m, 1H), 2.88 (dt, J=2.65, 12.95 Hz, 1H), 2.21-2.31 (m, 2H), 2.19 (s, 3H), 1.98-2.18 (m, 3H); MS (ESI): 454.19 [M+H]+; HPLC tR=0.85 min (TOF: polar—3 min).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[N:22]=[C:21]([NH:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH:20]=[N:19][CH:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[N:33]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CN1CCOCC1.O>CN1CCCC1=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:21]2[N:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[N:7]=[C:2]([N:36]6[CH2:37][CH2:38][CH2:39][N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:35]6)[CH:3]=[CH:4][CH:5]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(F)n3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(N4CCCN(C(=O)OC(C)(C)C)CC4)n3)n2)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of 6-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.479 mmol; 316.3 mg), tert-butyl 1,4-diazepane-1-carboxylate (0.958 mmol; 192 mg), and N-Methylmorpholine (1.20 mmol; 122 mg; 0.133 mL) in 1-methyl-2-pyrrolidinone (5 mL) in a sealed pressure vial was heated at 110° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (˜291 mg, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:10][CH:9]=1)[NH2:6].[CH3:26][O:27][CH2:28][CH2:29][C:30]1([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:12][CH:13]=1)[NH:6][C:35]([C:30]1([CH2:29][CH2:28][O:27][CH3:26])[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:36]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 84.1 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt (43.03 mmol, 11.75 g) and 1-(2-methoxyethyl)cyclopentane carboxylic acid (43.5 mmol, 7.5 g) in DMF (130 mL) was added HBTU (43.5 mmol, 16.5 g) and diisopropylethylamine (108.8 mmol, 19.02 mL) at room temperature. The clear solution was stirred 23 h at room temperature and was diluted with 200 mL of ethyl acetate. The ethyl acetate layer was washed successively with 0.5 N hydrochloric acid (2×100 mL), saturated sodium bicarbonate solution (2×100 mL), brine solution and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave 18.86 g (84%) of a white solid, mp 85-87° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.65 (s, 1H), 7.88 (d, 1H, J=19 Hz), 7.47-7.59 (m, 5H), 7.21 (d, 2H, J=19 Hz), 4.47-4.53 (m, 1H), 3.64 (s, 3H), 2.88-3.1 (m, 7H), 1.76-1.98 (m, 4H), 1.23-1.47 (m, 6H). HR MS C26H30Cl2N2O5): Obs. mass, 521.1586. Calcd. mass, 521.1610 (M+H).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[C:21]([NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][OH:39])[CH:31]=3)[C:20]=2[CH3:41])=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].O>N1C=CC=CC=1>[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[C:21]([NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][O:39][S:1]([CH3:4])(=[O:3])=[O:2])[CH:31]=3)[C:20]=2[CH3:41])=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OCCO)c3)c3ccccn23)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OCCOS(C)(=O)=O)c3)c3ccccn23)ccc1N
Temperature: -20 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
59 μl (0.77 mmol) of mesyl chloride are added to the solution of 0.34 g (0.69 mmol) of methyl 2-amino-5-[(1-{[3-(2-hydroxyethoxy)benzoyl]amino}-2-methylindolizin-3-yl)carbonyl]benzoate in 9 ml of pyridine at −20° C. under nitrogen. The reaction mixture is stirred for 2 hours at −20° C. and is then run into 100 ml of water. The precipitate obtained is filtered, washed thoroughly with water and dried under vacuum, to give 268 mg (70%) of a yellow powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:14][C:13](=[O:15])[CH2:12][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2ccc(C(F)(F)F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (130 mg, 0.308 mmol), EDC (83 mg, 0.432 mmol) and DMAP (75 mg, 0.617 mmol) in dry DCM (5 ml) was stirred at room temperature overnight. Aqueous 1N HCl was added to the reaction mixture and the organic phase was separated, washed with brine and dried over sodium sulfate. The solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel column (DCM/MeOH 96/4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (95 mg, 0.147 mmol, 48% yield). MS/ESI+ 645.03 [MH]+; [αD]=−2.157, c=0.510; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.67-7.85 (m, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.87 (dd, 1H), 7.03 (t, 1H), 6.61 (dd, 1H), 5.98 (dd, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 3.82 (d, 2H), 3.39 (dd, 1H), 3.19 (dd, 1H), 1.10-1.22 (m, 1H), 0.46-0.70 (m, 2H), 0.15-0.46 (m, 2H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1.Br[CH:16]([OH:18])[CH3:17].C(Cl)Cl.[OH-].[Na+]>O>[OH:18][CH2:16][CH2:17][NH:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCNC1CCc2cc3c(cc2C1)OCC3

Procedure:
7.7 g of 7-amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan, 5 g of bromoethanol, 40 ml of methylene chloride, 12 ml of 40% strength sodium hydroxide in water and 1 g of Triton B are stirred vigorously at room temperature for 48 hours. After separation following settling, the methylene chloride is evaporated off in the cold and the residue is taken up with ethyl ether, which is exhaustively extracted with hydrochloric acid. The alkalinized acid phases yield an oil having the expected structure.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[K+]>CN(C=O)C.O>[CH3:19][O:18][C:16]([C:15]1[S:14][C:2]2[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])cc(Cl)c2s1
Reaction time: 2 h

Procedure:
To a solution of 2,3-dichloro-5-nitrobenzaldehyde (10 g, 0.045 mol) and methyl mercaptoacetate (6.6 mL, 0.06 mol) in DMF (200 mL) was added KOH (6 g) in 50 mL water. After stirring for 2 h, the reaction mixture was poured in ice cold water and the mixture was extracted in ethyl acetate. The organic layer was washed with water and dried. The evaporation of the solvent gave crude product which was purified by repetitive washing with hexane to yield 7-chloro-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester, 12.3 g.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1/C=C/c1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C/c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
A solution of the Grignard reagent prepared from E-1-phenyl-2-(2 -bromophenyl)ethylene (8.56 g) and magnesium (0.96 g) in dry tetrahydrofuran (20 ml) was added dropwise over 30 minutes to a stirred solution of dimethyl oxalate (7.76 g) in dry tetrahydrofuran (70 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated to give the crude product as a pale yellow oil (17.22 g). Purification by column chromatography using dichloromethane and petrol (1:1) as eluant then evaporative distillation (0.07 torr, oven temperature 170° C.) gave E-methyl 2-(2'-phenylethenyl)phenylglyoxalate (2.01 g, 23% yield) as a yellow oil, pure by GC, 1H nmr (CDCl3) : delta 3.78 (3H, s), 6.88 (centre of 2 doublets, each 1 H, J 16Hz) p.p.m.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13]O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13][Cl:36])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CC#CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC#CCl)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(3-Hydroxyprop-2-ynyl)phenylacetic acid methyl ester (5.5 g, 0.027M) in tetrahydrofuran (110 ml) and carbon tetrachloride (110 ml) was added triphenylphosphine (7.81 g, 1.1 molar equivalents). The reaction mixture was heated at 60° C. for 3 h. After cooling, the solid obtained was removed by filtration and the mother liquors were concentrated under vacuum. The residue was purified by chromatography on silica gel using 50% diethyl ether in hexane as eluent to give the required product (5.35 g) as a colourless oil. δ (360 MHz, CDCl3) 3.62 (2H, s, CH2CO2CH3), 3.69 (3H, s, CH2CO2CH3), 4.36 (2H, s, CH2Cl), 7.23 (2H, d, J=8.2 Hz, ArH), 7.40 (2H, d, J=8.2 Hz, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([CH:15]=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C)C=O.O>[Br:29][C:15]1[C:16]2[C:21]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:9]3[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
9-(4-Bromophenyl)anthracene (6.3 g, 19 mmole) was dissolved in anhydrous dimethylformamide (DMF) (100 ml). To the resultant solution, a solution (15 ml) of NBS (3.7 g, 21 mmole, 1.1 eq) in anhydrous DMF was added and the obtained mixture was stirred at the room temperature for 7 hours and left standing for one night. After the reaction mixture was diluted with water (30 ml), the formed solid was separated by filtration and washed with methanol and a yellow solid (6.0 g, 77%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:15]([O:19][C:20](=[O:30])/[CH:21]=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20](=[O:30])[C@H:21]([CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: CCO[Si](CCCN)(OCC)OCC
Product: CCCCOC(=O)C[C@H](NCCC[Si](OCC)(OCC)OCC)C(=O)OCCCC

Procedure:
221.0 g (1.0 mol) of 3-aminopropyl-triethoxysilane and 228.0 g (1.0 mol) of maleic acid di-n-butyl ester were reacted by the same procedure used in Example 1. The viscosity of the clear, pale yellow liquid was about 30 mPa.s (23° C). Base titration showed an amine equivalent weight of about 462 g (theory: 449 g).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[C:10]([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCc1ccc(O)c(CC)c1C=O
Product: CCc1ccc(Oc2ccccc2)c(CC)c1C=O

Procedure:
2,6-Diethyl-3-phenoxy-benzaldehyde was prepared from 2,6-diethyl-3-hydroxy-benzaldehyde and phenylboronic acid in analogy to Example 219a): yellow oil; 1H-NMR (CDCl3): 1.20 (3H, t, CH3), 1.25 (3H, t, CH3), 2.93 (2H, q, CH2), 2.98 (2H, q, CH2), 6.91 (2H, d, 2×ArH), 7.00-7.10 (3H, m, 3×ArH), 7.28-7.38 (2H, m, 2×ArH), 10.6 (1H, s, CHO).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][C@@H:17]([CH3:19])[O:16][C@@H:15]([CH3:20])[CH2:14]2)=[CH:8][C:5]=1[C:6]#[N:7].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>C1COCC1>[C:6]([C:5]1[C:4]([NH:3][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[N:11][CH:10]=[C:9]([CH2:12][N:13]2[CH2:14][C@@H:15]([CH3:20])[O:16][C@@H:17]([CH3:19])[CH2:18]2)[CH:8]=1)#[N:7]
Reactant: C[C@@H]1CN(Cc2cnc(N)c(C#N)c2)C[C@H](C)O1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ncc(CN2C[C@@H](C)O[C@@H](C)C2)cc1C#N
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
Sodium hydride in mineral oil (60%, 25 mg, 0.61 mmol) was added to 2-amino-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)nicotinonitrile (100 mg, 0.41 mmol) in THF (2 mL) and the mixture was stirred for 5 minutes. Ethyl chloroformate (0.05 mL, 0.48 mmol) was added followed by additional sodium hydride (16 mg, 0.41 mmol) and the reaction stirred at room temperature for 3 h. The reaction was poured into a saturated solution of sodium bicarbonate (10 mL), extracted with EtOAc (3×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and stirred with potassium carbonate (170 mg) for 10 minutes, then poured into saturated sodium bicarbonate (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 0-100%, EtOAc/hexanes) afforded the title compound as a white powder (104 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.27 Hz, 6H), 1.26 (t, J=7.03 Hz, 3H), 1.69 (t, J=10.60 Hz, 2H), 2.67 (d, J=10.67 Hz, 2H), 3.51 (s, 2H), 3.54-3.62 (m, 2H), 4.17 (q, J=7.11 Hz, 2H), 8.12-8.24 (m, 1H), 8.56 (d, J=2.01 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: C=C(C(=O)O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: Nc1ccccc1SCC(C(=O)O)c1ccc(C(F)(F)F)cc1
Yield: 39.4 %

Procedure:
20.41 g of aminothiophenol were added all at once to a solution of 43 g of α-methylene-4-(trifluoromethyl)-benzene acetic acid [J. Med. Chem. (1969), Vol. 12 (3), p. 477 to 480] in 300 ml of ethanol, and the mixture was refluxed for 2 hours. The ethanol was evaporated off and the residue was taken up in 600 ml of ethyl ether and partially concentrated to 300 ml. 200 ml of isopropyl ether were added with concentration to 100 ml and cooled for 30 minutes in ice-cooled water. The crystallized product was separated off, washed with isopropyl ether and dried under reduced pressure at 100° C. to obtain 21.9 g of expected product melting at approx. 138° C.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C1COCC1.CN(C=O)C>[Ni].O>[F:17][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(F)(F)CC2)nc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(N2CCC(F)(F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The product from Example 135A (4.56 g, 18.75 mmol) and solvent THF (20 mL)/DMF were added to Ra—Ni 2800, water slurry (4.56 g, 78 mmol) in a 250 mL SS pressure bottle and stirred for 2 hr at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and washed with MeOH. The filtrate was concentrated and dried under vacuum to afford the title compound (3.40 g, 85%). 1H NMR (400 MHz, DMSO-D6) δ 2.03-1.88 (m, 4H), 3.49-3.38 (m, 4H), 4.61 (s, 2H), 6.73 (d, J=8.8, 1H), 6.93 (dd, J=2.9, 8.8, 1H), 7.61 (d, J=2.6, 1H). MS (ESI) m/z 214 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[S:19][C:20]([CH3:22])=[N:21][C:15]=3[CH2:14][CH2:13]2)[N:3]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[S:19][C:20]([CH3:22])=[N:21][C:15]=3[CH2:14][CH2:13]2)[C:5]=1[N+:9]([O-:11])=[O:10])[CH3:24]
Reactant: CCI
Reactant: Cc1nc(N2CCc3nc(C)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCc3nc(C)sc3CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 19.3 %

Procedure:
A suspension of 0.120 g (0.373 mmol) of 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one (example 1), of 0.070 g (0.45 mmol) of the ethyl iodide and of 0.077 g (0.56 mmol) of potassium carbonate in 1.0 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was then chromatographed on silica gel using a 95:5 v/v mixture of dichloromethane and methanol as eluent giving in a first fraction 0.025 g (0.072 mmol, yield 19%) of the 6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine as yellow amorphous solid; MS: [M+H]+=350.
Reaction SMILES: C(CN)O.C([O:12][C:13]1[CH:14]=[C:15]([C:24](=[O:28])[CH:25](O)O)[C:16]2[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=2[CH:23]=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:40][CH2:25][CH:24]([C:15]2[C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=[C:13]([OH:12])[CH:14]=2)[OH:28])([CH3:38])[CH3:39])=[CH:34][CH:35]=1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)C(O)O)N1
Reactant: CC(C)(N)Cc1ccc(Br)cc1
Solvent: NCCO
Product: CC(C)(Cc1ccc(Br)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The preparation of the ethanolamine and debenzylation were carried out as described in Example 19 from 300 mg (0.91 mmol) of 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 250 mg (1.09 mmol) of 2-(4-bromophenyl)-1,1-dimethylethylamine. Beige solid. Yield: 54 mg (14%); mass spectrometry: [M+H]+=435, 437.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH:26]4[CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: NC1CC1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NCc2nnc(CNC3CC3)n2-c2ccc(Cl)cc21

Procedure:
In the manner given in Example 1,potassium iodide and 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-chloro-1-[(cyclopropylamino)methyl]-6-(2,6-difluorophenyl)4H-s-triazolo-[4,3-a][1,4]benzodiazepine.