Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.CCN(CC)CC.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>O1CCOCC1.[Cl-].[Na+].O>[O:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: NC1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(NC2CCOCC2)cn1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
Methyl 5-chloro-2-pyrazinecarboxylate (507 mg, 2.94 mmol), Et3N (1.08 mL, 7.64 mmol) and 4-aminotetrahydropyran (0.40 mL, 3.82 mmol) were dissolved in dioxane (5 mL) and heated in a microwave reactor at 100° C. for 20 min. Water (50 mL) and brine (25 mL) were added and the reaction mixture was extracted into EtOAc (2×100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (236 mg, 33.9%) as a yellow oil. LCMS (ES+): 238.2 [MH]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:5])C.O1CCOCC1.Cl>O>[OH:5][C:4]([CH:6]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3cccc(O)c3)coc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1ccc2c(=O)c(-c3cccc(O)c3)coc2c1)C(=O)O
Temperature: 0 °C
Yield: 90.5 %

Procedure:
A mixture of 3.0 g of 7-(1-ethoxycarbonylethyl)oxy-3-(3-hydroxyphenyl)-4H-1-benzopyran-4-one, 90 ml of dioxane, 120 ml of water and 15 ml of hydrochloric acid was refluxed for 2.5 hours, poured into ice water and extracted with ethyl acetate. The extract was washed with water and concentrated and the residue was recrystallized from ethyl acetate-dichloroethane to give 2.5 g of 7-(1-hydroxycarbonylethyl)oxy-3-(3- hydroxyphenyl)-4H-1-benzopyran-4-one as white crystals. m.p. 218°-219° C.
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15].P(Cl)(Cl)[Cl:17]>CC(C)=O>[Cl:17][CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15]
Reactant: ClP(Cl)Cl
Reactant: O=C1C=C(c2ccccc2)C(=O)N1CO
Solvent: CC(C)=O
Product: O=C1C=C(c2ccccc2)C(=O)N1CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 200 ml of acetone was suspended 20.3 g of N-hydroxymethyl-α-phenylmaleimide and then 4.6 ml of phosphorus trichloride was added in one portion at room temperature. After the mixture was stirred for 30 minutes, 5.0 ml of phosphorus trichloride was further added. After stirring for another one hour, the reaction solution was poured into ice-water and the crystals thus separated were collected by filtration. The crude crystal was dried under reduced pressure and then recrystallized from n-theptane/ethyl acetate to afford 12.1 g of N-chloromethyl-α-phenylmaleimide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.CC(N(C)C)=O>[C:26]1([S:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:12]([OH:14])=[O:13])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc2ccccc2c1C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Example 42B (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M chlorotrimethylsilane in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of benzenesulfonyl chloride (0.042 g, 0.24 mmol) in dimethylacetamide (1 mL), shaken for 16 hours at ambient temperature, and concentrated. The concentrate was acidified to pH 1.0 with 5% aqueous HCl and extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 328 (M+H)+, 345 (M+NH4)+, 350 (M+Na)+; (ESI(−)) m/e 326 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.30 (br s, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.78 (dd, 2H), 7.63-7.50 (m, 5H), 7.31 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=[CH:33][C:34]#[N:35])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)c1
Yield: 97.6 %

Procedure:
(3,5-Dimethoxyphenyl)-(2,3,4-trimethoxyphenyl)methanone (11.15 g, 3.46 mmol), cyanomethylphosphonic acid diethyl ester (1.09 ml, 6.92 mmol) in anhydrous THF (8 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 6.92 ml, 6.92 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3(3,5-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as a pink oil (1.20 g, 98%): 1HNMR (DMSO-d6) δ 7.00-6.84 (m, 2H, Ar), 6.62-6.59 (m, 1H, Ar), 6.45 (d, J=2 Hz, 2H, Ar), 6.01 (s, 0.51H, double bond proton), 3.87-3.44 (multiple singlets, 15H, 50CH3); 13C NMR (CDCl3) δ 160.9, 160.8, 160.7, 160.2, 155.5, 155.4, 152.5, 151.8, 142.7, 142.6, 141.4, 140.5, 126.2, 125.8, 125.4, 124.1, 118.0, 117.8, 107.2, 107.0, 105.7, 102.0, 101.9, 96.8, 96.6, 61.1, 61.0, 60.9, 56.2, 55.7, 55.6; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.53; H, 5.84; N, 3.88.
Reaction SMILES: [CH3:1][C@@:2]12[C:19]([CH3:21])([CH3:20])[C@@H:5]([C:6]3[C:7](=[O:18])[N:8]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.S(OC)(O[CH3:26])(=O)=O>[OH-].[Na+].O>[CH3:26][N:9]1[C:10]2[C@@:2]3([CH3:1])[C:19]([CH3:21])([CH3:20])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:18])[N:8]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH3:26][O:18][C:7]1[N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:9]=[C:10]2[C:6]=1[C@@H:5]1[C:19]([CH3:21])([CH3:20])[C@@:2]2([CH3:1])[CH2:3][CH2:4]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c2c(nn1-c1ccc(C)cc1)[C@]1(C)CC[C@H]2C1(C)C
Product: Cc1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %
Yield: 20 %

Procedure:
(4S,7R)-7,8,8-Trimethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 9; 400 mg, 1.4 mmol) was dissolved in 1 M NaOH (5 mL) and dimethyl sulfate (0.14 mL, 1.46 mmol) was added. The mixture was stirred at room temperature overnight and then diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-100% ethyl acetate/hexanes to give (4S,7R)-1,7,8,8-tetramethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 20%) as an off-white solid and (4S,7R)-3-methoxy-7,8,8-trimethyl-2-p-tolyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (134 mg, 32%) as a yellow solid. ES(+)-MS (M+H) 297.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH3:27])[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: Cc1ncc[nH]1
Product: COc1cc(-n2ccnc2C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 12 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (190 mg, 0.54 mmol) was converted using 2-methyl-imidazole instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=20:70:10:0 to 0:90:0:10, 27 mg, 12%) which was obtained a light-brown solid. MS: m/e=414.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:15]3[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=3[C:21](=[O:22])[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([N+:25]([O-])=O)=[CH:10][CH:11]=2)[C:6]1=[O:28].CO.C(OCC)(=O)C>O1CCCC1>[NH2:25][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[C:21](=[O:22])[C:20]4[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16][C:15]=4[C:14]=3[N:5]([CH2:4][CH2:3][CH2:2][Br:1])[C:6]2=[O:28])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc([N+](=O)[O-])ccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc(N)ccc12
Reaction time: 24 h
Yield: 58.9 %

Procedure:
6-(3-Bromopropyl)-9-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (80, 1.00 g, 2.26 mmol) was dissolved in tetrahydrofuran (60 mL), methanol (20 mL), and ethyl acetate (30 mL) and transferred to a Parr shaker flask. The reaction vessel was purged with argon for 10 min and then palladium-charcoal (10%, 20 mg) was added. The reaction mixture was shaken for 24 h under an atmosphere of hydrogen (60 psi). The solid was filtered off, the solvent removed under vacuum, and the compound purified by silica gel column chromatography, eluting with ethyl acetate. The product was obtained as a brown solid (0.55 g, 59%): mp 330° C. (dec). IR (Film) 3367, 1696, 1655, 1506, 1480, 1431, 1293, 1229, 1016, 834, 787, 665 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=8.6 Hz, 1H), 7.67-7.62 (m, 2H), 7.06 (d, J=2.5 Hz, 1H), 7.0.1-6.94 (m, 2H), 4.51 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.75 (dd, J=7.5 Hz, J=6.6 Hz, 2H), 2.30 (br p, J=8.5 Hz, 2H); EIMS m/z (rel intensity) 413 (M+, 46), 333 ([M-HBr)]+, 100); HRESIMS m/z calcd for C20H17N2O3Br, 413.0501 (MH+). found, 413.0505 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O>[CH2:29]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)[CH3:30]
Reactant: CCI
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)CC)cc12
Temperature: 120 °C
Yield: 35.9 %

Procedure:
To a solution of (R)-3-(pyrrolidin-2-ylmethyl)-5-(2-ethylsulphonylethyl)-1H-indole (0.27 g, 0.8 mmol) in dimethylformamide (dried over 4A sieves) (5 mls), was added sodium carbonate (90 mgs) and ethyl iodide (0.07 mls, 0.88 mmol) at room temperature. The mixture was heated at 120° C. under nitrogen for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with water (3x), dried (Na2SO4) and evaporated in vacuo to give an oil. Purification by column chromatography on silica gel, eluting with CH2Cl2 : EtOH: NH4OH (90:10:0.5) gave the title compound as a gum (100 mgs). Anal. Calcd for C19H28N2O2S·1/4 CH2Cl2. 1/2 H2O: C,61.04; H,7.85; N,7.40. Found: C,60.80; H,7.69; N,7.48. [α]25D =+60° (c=0.1, MeOH)
Reaction SMILES: ClC1C=C(F)C=CC=1[C@H]1[C:14]([C:15]([O-:17])=[O:16])=[C:13]([CH2:18][Br:19])[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH:29]=O.Cl[C:36]1C=C(F)C=CC=1C=O>>[Br:19][CH2:18][C:13]1[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10][C@@H:29]([C:28]2[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=2)[C:14]=1[C:15]([O:17][CH3:36])=[O:16]
Reactant: O=C([O-])C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)cc1Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)c(F)c1

Procedure:
Methyl (4S)-6-(bromomethyl)-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 114a was prepared in analogy to compound C with procedures shown in Example 1 by using 3,4-difluoro-benzaldehyde instead of and 2-chloro-4-fluoro-benzaldehyde.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH3:10]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH:8]([Br:1])[CH2:9][CH3:10]
Reactant: BrBr
Reactant: CCCC(=O)C(C)(C)C(=O)OC
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of bromine (24 g, 150 mmol) in chloroform (30 mL) is added to 2,2-dimethyl-3-oxo-hexanoic acid methyl ester (25.9 g, 150 mmol) in chloroform (126 mL) at 0–5° C. dropwise. After the addition of bromine, the mixture is allowed to warm up to room temperature slowly and stirred overnight. The reaction is then quenched by ice water, the layers are separated. The organic layer is washed with cold water and brine, dried over sodium sulfate. Concentration gave the title compounds (36.9 g), which is used for next step without further purification.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:18]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Reactant: CC(C)CCN
Product: CC(C)CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 77.6 %

Procedure:
3.6 g of D-galactose, 2.3 g of isopentylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.5 g of 1-(2-chloroethyl)-3-isopentyl-3-D-galactopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH:20]([CH2:28][OH:29])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(Cl)Cl>[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH:20]([CH:28]=[O:29])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC1CN(Cc2ccccc2)CC1c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
To a solution of 0.31 mL (3.6 mmol) of oxalyl chloride in 20 mL of CH2Cl2 at −78° C. was added 0.51 mL (7.2 mmol) of DMSO and the reaction mixture was stirred. After 10 min., a solution of 0.49 g (1.8 mmol) of 1-benzyl-3-(RS)-hydroxymethyl-4-(SR)-(3-thienyl)pyrrolidine in 20 mL of CH2Cl2 was then added. After stirring for 10 min. at −78° C., the reaction was allowed to warm to rt. The reaction mixture was poured into ether and extracted twice with sat'd NaHCO3 solution and once with sat'd NaCl solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.49 g of the title compound. 1H NMR (CDCl3) δ9.75 (d, 1H, J=2.1 Hz), 7.27-7.36 (m, 6H), 7.03-7.07 (m, 2H), 3.78 (q, 1H, J=6.8 Hz), 3.72 (d, 1H, J=13.1 Hz), 3.68 (d, 1H, J=12.8 Hz).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:18][CH2:17]1
Reactant: OC(CBr)C1COc2ccccc2O1
Reactant: O=C1c2ccccc2C(=O)N1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
Erythro, 1-(1,4-benzodioxan-2-yl)-2-bromoethanol (1.29 g, 0.005 m) and 2-(piperid-4-yl)-1H-isoindole-1,3-(2H)dione hydrochloride (1.33 g, 0.005 cm3) in ethanol (75 cm3) with triethylamine (3.03 g, 0.03 cm3) were refluxed for 18 hours. The solution was cooled and the solvent evaporated. the residue was dissolved in chloroform and then washed twice with water, dried (MgSO4) and evaporated. The residue was dissolved in isopropyl alcohol and acidified with ethanolic HCl. The crystallised material was filtered to give the title compound as the hydrochloride salt m.p. 235°-237° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH2:21])[CH3:17].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17]
Reactant: BrCCCCCOCCc1ccccc1
Reactant: CCOC(CN)OCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(CNCCCCCOCCc1ccccc1)OCC
Temperature: 78 °C
Reaction time: 48 h
Yield: 11.2 %

Procedure:
2-(5-Bromopentoxy)ethylbenzene (1.5 g) was dissolved in ethanol (30 mL) and treated with 2,2-diethoxyethylamine (0.86 g) and diisopropylethylamine (1.8 mL) at room temperature. The reaction was stirred at 78° C. for 48 hours and was then poured into ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (0.2 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:11][CH:10]2C([O-])=O)=[CH:5][C:4]=1[CH3:15])#[N:2].CC[O-].[Na+].O>C(O)C>[CH3:15][C:4]1[CH:5]=[C:6]([CH2:9][CH:10]=[O:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1cc(C2OC2C(=O)[O-])ccc1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(CC=O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 5 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (5 mmol) in 4 mL of ethanol was added and stirred at 0° C. for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[CH:24]=[C:23](C(OCC)=O)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-:30].[Li+].C1[CH2:36][O:35]CC1.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[C:24]([C:36]([OH:35])=[O:30])=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc2c1
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CCc1[nH]c(C(=O)NC2CN(c3nc4cccc(C(=O)O)c4s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 83 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-1,3-benzothiazole-6-carboxylate obtained in Example (225d) (124 mg, 0.29 mmol) was dissolved in methanol (3 mL). A 2 N aqueous lithium hydroxide solution (1.43 mL, 2.86 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. THF (1.5 mL) was added, followed by further stirring for three hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (2.5 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 96 mg of the title compound as a white solid (83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.CCOC(C)=O>[N:42]([CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)[C:16]3=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]3[N:14]=2)[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=1)=[N+:43]=[N-:44]
Reactant: N#Cc1cc(CO)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: N#Cc1cc(CN=[N+]=[N-])c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 70 °C
Yield: 62.6 %

Procedure:
A mixture of 2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 402)(120 mg, 0.315 mmol), diphenylphosphoryl azide (0.102 mL, 0.473 mmol) and DBU (0.071 mL, 0.473 mmol) in dry dioxane (3 mL) was heated at 70° C. for 20 hr. It was diluted with EtOAc and washed with water. The aqueous phase was washed with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by radial silica gel chromatography eluting with DCM containing 0 to 3% MeOH afforded 2-((3-(azidomethyl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as a white solid.