Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[CH:8]=1.O.[OH-].[Na+]>C(OCC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH:8]=1
Reactant: COC(=O)/C=C/c1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCc1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice cold mixture of lithium aluminium hydride (28 mg, 0.74 mmol) in dry diethyl ether (20 ml) was added dropwise methyl E-3-(3-pyridyl)acrylate (100 mg, 0.61 mmol) under argon. The resulting mixture was allowed to warm up to room temperature and stirred for 12 h. Water (0.1 ml), 15% aqueous sodium hydroxide (0.1 ml) and water (0.3 ml) were added sequentially over 0.5 h and the mixture allowed to stir for 1 h. The resulting suspension was filtered and the filtrate concentrated under reduced pressure. Flash chromatography (flash silica gel; 10% methanol in ethyl acetate) gave 3-(3-pyridyl)-1-propanol, which was discarded, and E-3-(3-pyridyl)-1-prop-2-enol (55 mg, 67%) as a colourless oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][O:10][CH:9]([CH3:13])[CH2:8]1)[S:5][CH3:6])#[N:2].SC[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>CO>[NH2:2][C:1]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH3:13])[CH2:8]2)[S:5][C:6]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CS
Reactant: CSC(=NC#N)N1CCOC(C)C1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(N2CCOC(C)C2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of methyl N-cyano-2-methylmorpholine-4-carbimidothioate (1.2 g, 6 mmol), methyl 2-mercaptoacetate (0.64 g, 6 mmol) and triethylamine (1.2 g, 12.0 mmol) in methanol (50 mL) was stirred at ambient temperature overnight. Solvent was removed. The residue was dissolved in dichloromethane, washed with water and brine. The organic layer was concentrated to give the desired product (crude, 1.4 g, 93%). 1H NMR (300 MHz, CDCl3) δ 5.81 (br, 2H), 3.97˜3.94 (m, 1H), 3.75 (s, 3H), 3.69-3.59 (m, 3H), 3.28-3.14 (m, 1H), 2.87-2.80 (m, 1H), 1.22 (d, J=6.0 Hz, 3H); LC-MS: 258 (MH+).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7]([O:13]C(=O)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.[C-:31]#[N:32].[Na+]>CS(C)=O>[C:31]([C:2]1[O:6][C:5]2[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1)#[N:32]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2c(C#N)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 3.5 h

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzo[b]furan (25 mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL) under nitrogen at room temperature was stirred for 3.5 hours (tlc), quenched with saturated ammonium chloride solution and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over magnesium sulfate and solvent was distilled to afford the crude material which was purified over silica gel column (eluent-Hexane: diethyl-ether 1:1 to 0:100) to afford 2-cyano-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzo[b]furan as pale cream solid; (13 mg, 65%); 1H NMR (300 MHz, CDCl3) δ: 7.29(d, 1H, J=8.71 Hz), 7.19(s, 2H, benzoyl Hs), 6.06(d, 1H, J=8.77 Hz), 5.82(b, 1H, OH), 3.99(s, 3H, OMe), 3.96(s, 3H, OMe), 3.88(s, 6H, 2×OMe).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C1C=CC2N(O)N=[N:18]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>CC#N.[Cl-].[Na+].O.O.CCOCC>[F:1][C:2]([F:11])([F:10])[O:3][CH2:4][CH2:5][CH2:6][C:7]([NH2:18])=[O:8]
Reactant: O=C(O)CCCOC(F)(F)F
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC#N
Solvent: O
Product: NC(=O)CCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A mixture of 4-(trifluoromethoxy)butanoic acid (1.0 g, 5.81 mmol) and HOBt (1.157 g, 7.55 mmol) in MeCN (20 mL) was treated with EDC (1.448 g, 7.55 mmol) and stirred at RT for 2 h. Ammonium hydroxide (˜15M, 0.7 mL, ˜10.5 mmol) was added and the mixture stirred at RT for 20 h. The mixture was treated with Et2O, water and brine, the layers separated and the organic layer dried over Na2SO4 and concentrated to afford 4-(trifluoromethoxy)butanamide (1.024 g, 103%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.30 (s, 1H), 6.78 (s, 1H), 4.04 (t, J=6.4 Hz, 2H), 2.13 (t, J=7.4 Hz, 2H), 1.82 (m, 2H).
Reaction SMILES: [C:1](OCCCl)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:10]([O:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[CH2:11][OH:12]>C(OCC)C>[C:1]([O:12][CH2:11][C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)OCCCl
Reactant: CC(C)OC(=O)CO
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloroethyl lactate (1.91 g, 12.5 mmol) and various amounts of isopropyl glycolate (1.48, 2.22 and 2.95 g; 12.5, 18.8 and 25.0 mmol, respectively) in 25 mL of ethyl ether containing 0.125% tert-butylbenzene were added to 1.75 g Lipase P30 powder and the reaction mixtures were agitated on an orbital shaker (175 RPM) at room temperature for 48 hr. After 48 hr, conversion of 2-chloroethyl lactate to the title compound was estimated (by GC, Method A) to be 30, 38 and 44% with 1.0, 1.5 and 2.0 equivalents of isopropyl glycolate, respectively. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C7H10O5Tms (M-CH3) 247.1001, obsd 247.0990. A portion of one of the reactions was partially purified by flash chromatography (ethyl acetate/hexane, 20/80) to give a mixture of 2-chloroethyl lactate and the title compound. The partially purified mixture was separated by flash chromatography (CH2Cl2 /isopropanol, 99/1) to give the title compound: 1H NMR δ1.27 (d, 6H, J=6.3 Hz), δ1.49 (d, 3H, J=7.0 Hz), δ3.28 (d, 1H, J=4.6 Hz), δ4.42 (m, 1H), δ4.60 (d, 1H, J=15.8 Hz),δ4.71 (d, 1H, J=15.8 Hz), δ5.09 (m, 1H, J=6.3 Hz); 13C NMR 20.3, 21.7, 61.5, 66.9, 69.6, 166.8, 174.9.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:49][CH:48]4[CH:44]([CH2:45][NH:46][CH2:47]4)[CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH:44]4[CH:48]([CH2:47][NH:46][CH2:45]4)[CH2:49]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CC4CNCC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(N4CC5CNCC5C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (13.8 mg, 0.0200 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product, which was further purified by preparative HPLC to afford the desired product (2.1 mg, 13.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 571 (M+1). 1H NMR (400 MHz, CD3OD δ 11.92 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.65 (m, 2H), 7.48 (d, 1H), 7.41 (m, 1H), 7.26 (m, 2H), 6.26 (d, 1H), 3.74 (d, 2H), 3.57 (m, 2H), 3.08-3.38 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1c(F)cccc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1c(F)cccc1F

Procedure:
To a suspension of 2,6-difluorobenzaldehyde (374.7 mg, 2.64 mmol), 1,1-dimethylnitroethane (541.6 mg, 5.25 mmol) and zinc (517.0 mg, 7.91 mmol) in ethanol (3.0 ml) was added acetic acid (940.5 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/2-2/1).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([NH:18][C:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[N:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:42])[CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:18]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C[C@@H](COC(C)=O)NC(=O)c2ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](COC(C)=O)C2
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of (2S)-1-acetoxy-3-(3,4-dimethoxyphenyl)-2-{2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]isonicotinoylamino}propane (150 mg) in acetonitrile (5 ml) is added phosphorus oxychloride (0.29 ml), and the mixture is heated under reflux overnight. The reaction mixture is cooled to room temperature, and neutralized with an aqueous sodium hydrogen carbonate solution. The mixture is extracted with chloroform, and the extract is washed, dried, and concentrated. The residue is crystallized from ethyl acetate to give (3S)-4-(3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (136 mg), as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C@@H:14]([OH:17])[CH2:15][OH:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:20](OC)([CH3:22])[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:21][C:20]1([CH3:22])[O:17][C@H:14]([CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:15][O:16]1
Reactant: COC(C)(C)OC
Reactant: OC[C@H](O)CCc1cc(-c2ccccc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reaction time: 3 h

Procedure:
To a solution of (R)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g, 10.76 mmol) in acetone (50 mL), were added 2,2-dimethoxypropane (11.21 g, 108 mmol) and PTSA (0.185 g, 1.076 mmol) at room temperature. After stirring for 3 h, the reaction was concentrated under reduced pressure. The resulting residue was poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=273.4 [M+H]+.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:37].N1CCCC1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:37])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 279.1 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.212 g, 0.56 mmol, 1.0 eq), and triethylamine (96 uL, 65 mg, 0.65 mmol, 1.15 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (77 uL, 80 mg, 0.59 mmol, 1.05 eq) followed by pyrrolidine (94 uL, 80 mg, 1.13 mmol, 2.0 eq). Workup as above provided 205 mg (85%) of L-isoleucine, N-[1-[2-(1-pyrrolidine)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(I)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cccc(F)c2)ccc1Br

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.065 g, 0.080 mmol), 1-bromo-4-iodo-2-methoxybenzene (CombiBlocks, 0.250 g, 0.799 mmol), 3-fluorophenylboronic acid (0.123 g, 0.879 mmol) and potassium phosphate (0.848 g, 3.99 mmol) in dioxane (2.130 ml)/water (1.065 ml) was heated to 90° C. overnight. The reaction was diluted with DCM and separated from the aqueous via phase separator (Radleys Discovery Technologies). After concentration in vacuo, the material was purified via MPLC (12-g Redi Sep Gold), eluting with 0-100% ethyl acetate in heptanes to yield, after concentration, 4-bromo-3′-fluoro-3-methoxy-1,1′-biphenyl as an orange oil, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH:17]1[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:17]1([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC3CCC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), (bromomethyl)cyclobutane (58 mg, 0.39 mmol, Aldrich, Cat. No. 226998), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water. The product was extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 64 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([CH3:35])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:34])=[C:28]([CH3:35])[CH:27]=1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(C)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-methyl-4-isocyanato-benzoic acid methyl ester in toluene for 4 d under reflux conditions to give the title compound as white solid. MS: m/e=483.4 [M+H+].
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH:8]1([C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([OH:18])[N:12]=2)[CH2:10][CH2:9]1>[OH-].[Na+]>[CH:8]1([C:11]2[N:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:6][CH3:7])[N:16]=2)[CH2:10][CH2:9]1
Reactant: Oc1cc(O)nc(C2CC2)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)nc(C2CC2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
76 g (0.6 mol) of dimethyl sulphate were added dropwise to a solution of 76 g (0.5 mol) of 2-cyclopropyl-4,6-dihydroxy-pyrimidine in 250 ml of 2 N sodium hydroxide solution at 50° C. The pH value of the reaction solution was kept at 8 to 8.2 by simultaneously adding 2 N sodium hydroxide solution. The mixture was then stirred at 50° C. for a further 2 hours, control of the pH being continued. The mixture was then cooled to 0° C. and the product which had precipitated was filtered off. 33 g (40% of theory) of 2-cyclopropyl-4-hydroxy-6-methoxy-pyrimidine were obtained in this manner in the form of colorless crystals with a melting point of 186° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23](O)=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(Br)ccn1N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 93 %

Procedure:
The title compound was prepared from methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (2.83 g, 12.9 mmol) and (S)-4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanoic acid (4.0 g, 12.9 mmol) following the experimental procedure described in Preparation 73a. 6.12 g (93% yield) of the desired compound were obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:11]2=[CH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:10]2[CH2:9][CH:8]1[C:19](OCC)=[O:20].[Cl-].[NH4+]>O1CCCC1>[OH:20][CH2:19][CH:8]1[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]2[CH2:7]1
Reactant: CCOC(=O)C1Cc2cc3ccccc3n2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1Cc2cc3ccccc3n2C1
Reaction time: 1 h
Yield: 58 %

Procedure:
4 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran were added to a solution of 750 mg of ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate in 30 ml of tetrahydrofuran. After 1 hour, 30 ml of saturated ammonium chloride solution were added and the mixture was evaporated. The residue was extracted with dichloromethane and the organic extract was dried and evaporated. Crystallization of the residue from diethyl ether/petroleum ether gave 355 mg of 2,3-dihydro-2-(hydroxymethyl)-1H-pyrrolo[1,2-a]indole of melting point 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([Br:14])[C:8](N)=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[C-:21]#[N:22].[Na+].Cl>S(=O)(=O)(O)O.O.[Cu]>[Br:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([Br:14])[C:8]([C:21]#[N:22])=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [C-]#N
Reactant: Nc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: N#Cc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br
Reaction time: 2 h
Yield: 54.7 %

Procedure:
2,4,6-Tribromo-5-amino-isophthalic acid (232 g; 0.555 mole) is dissolved in concentrated sulfuric acid (500 ml) and the solution is then cooled by means of an ice-bath to a temperature between 0° and 5° C. Sodium nitrite (77 g; 1.11 mole) is then added portionwise over 1 hour while maintaining the temperature at 0°-5° C., and the mixture is stirred for a further 2 hours at that temperature. The mixture is then slowly poured over ice, with stirring, and the excess sodium nitrite is destroyed with a sufficient amount of urea solution. While still maintaining the temperature at 0°-5° C., the suspension is neutralized at pH 6 by addition of 5N sodium hydroxide. The mixture is then added to a solution of cuprous chloride (69 g; 0.694 mole) and sodium cyanide (89 g; 1.82 mole) in 1 liter water, and the solution is stirred overnight at room temperature. The pH of the solution is adjusted to 3 by addition of hydrochloric acid, the copper salt precipitate is suction filtered, and the pH is adjusted to 1 with hydrochloric acid. The solution is cooled in an ice-bath and stirring is maintained for a further 16 hours. The resulting precipitate is suction filtered; it is then taken up into 400 ml water, with stirring, plus a sufficient amount of sodium hydroxide for dissolution and neutral pH. The solution is decolorized by stirring for 1 hour with charcoal 3 SA, after which the charcoal is filtered off, and the material is precipitated with dilute hydrochloric acid to give, after suction filtering and washing with a small amount of water, 130 g of white product (Yield: 55%).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=2[CH:15]=1>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of 3H-imidazo[4,5-b]pyridine (2.99 g, 25 mmol) in DMF (100 mL) was added sodium hydride (60% in mineral oil, 1.0 g, 25 mmol) slowly at 0° C. After the reaction mixture was stirred at rt for 20 min, it was treated with a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Step 3 of this Example (4.8 g, 21 mmol) in DMF (20 mL) at 0° C. The reaction mixture was then stirred at rt overnight. The mixture was quenched with 3 mL of saturated aq NH4Cl and concentrated under reduced pressure. The residue was diluted with 600 mL of EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure The crude product was purified on a silica gel column using a mixture of MeOH—CH2Cl2 (1:30, v/v) as eluent to give 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a tan solid (2.5 g, 38%). The regiochemistry of the alkylation was determined by a 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.38 (dd, J=1.2, 4.8 Hz, 1H), 8.11 (dd, J=1.3, 8.1 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.8, 8.0 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.