Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Cl)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: C1COCCN1
Product: O=c1c2[nH]c(N3CCOCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
1,3-Di-cyclopropylmethyl-8-morpholino xanthine was prepared from 1,3-di-cyclopropylmethyl-8-chloro-xanthine (0.3 g, 0.001 mol) and morpholine (0.2 g, 0.0022 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C., yield 0.09 g (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:31][NH:32][C:33]([CH:35]1[CH2:37][CH2:36]1)=[O:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:41][C:40]1[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33]([CH:35]2[CH2:36][CH2:37]2)=[O:34])=[CH:29][C:28]=1[NH:27][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 13.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-36, 0.085 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) and dry toluene (5.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.1 Hz, 4H), 1.61 (m, 1H), 4.11 (s, 3H), 4.28 (d, J=5.4 Hz, 2H), 7.04 (d, J=6.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.71-7.79 (m, 4H), 7.88 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.44 (s, 1H), 8.67 (m, 1H), 10.53 (s, 1H), 12.82 (br s, 1H); MS (m/z): 587.96 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccc(F)cc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.92 g, 4.483 mmol) and 1,4-Difluoro-2-nitro-benzene (0.486 ml, 4.483 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (1.2 g, 8.96 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH:39][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(Cl)c1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3cccc(Cl)c3)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (200 mg, 0.37 mmol), 3-chlorobenzylamine (74 mg, 0.52 mmol), Pd2(dba)3 (21 mg, 10% mmol), DavePhos (29 mg, 20% mmol), t-BuONa (50 mg, 0.52 mmol) and dioxane (10 mL). The mixture was stirred at 120° C. under an atmosphere of N2 for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:MeOH, 100:1) to give [3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 110 mg, 50%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[C:10]3[CH2:11][CH2:12][C:13](=[O:18])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[C:10]4[CH2:11][CH2:12][C:13](=[O:18])[C:14]=4[CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C1CCc2c(Oc3cncc(Cl)n3)cccc21
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc4c3CCC4=O)n2)cc(OC)c1OC
Yield: 23 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-4-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (71 mg). Yield: 23%. 1H NMR (250 MHz, DMSO-d6) δ 2.69 (t, 2H, H3, J=3.7 Hz), 2.98 (t, 2H, H2, J=5.2 Hz), 3.43 (s, 6H, [CH3O]3+5), 3.59 (s, 3H, [CH3O]4), 6.75 (s, 2H, Harom2′+6′), 7.56-7.62 (m, 3H, Harom), 7.90 (s, 1H, HPz 5), 8.04 (s, 1H, HPz 3), 9.62 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].CCO.C1COCC1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(CC)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(CC)n1C
Yield: 196.7 %

Procedure:
A solution of 20% Pd(OH)2/C (6.95 g) and 3-(4-benzyloxy-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (23.173 g, 59.65 mmol, prepared in example E-80a or E-80b) in a 1/2 EtOH/THF solution (300 mL) is placed under 50 PSI of H2 at room temperature for 3.5 hours. The reaction mixture is combined with another reaction mixture of the same scale, and the combined reaction mixtures are filtered through Hyflo, washing with EtOAc. The filtrate is concentrated in vacuo to afford a white residue. The white residue is dissolved in a minimal amount of EtOAc, then treated with excess hexanes, causing a precipitate to form. The resulting white solid is recovered by vacuum filtration, washing with hexanes and drying under vacuum to afford the title compound (35.01 g, 98% yield) as a white solid: 1H NMR (500 MHz; CDCl3) δ 7.23 (d, 2H), 6.83 (d, 2H), 5.46 (s, 1H), 4.11 (q, 2H), 3.87 (s, 3H), 2.84 (q, 2H), 1.30 (t, 3H), 1.06 (t, 3H); MS(ES): m/z 299.1 (M++H), 297.1 (M−H−). Anal. Calcd. For C17H18N2O3: C, 68.44; H, 6.08; N, 9.38. Found C, 68.18, H, 6.06; N, 9.34.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:38][CH2:37][CH2:36][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Reactant: NCCN1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN1CCCC1)COc1ccccc1-3

Procedure:
To a solution of methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 9, Step 4) in 1,2-dichloroethane (0.11 M), was added 1.3 eq of (2-pyrrolidin-1-ylethyl)amine and 1.5 eq of HOAc, followed by 1.5 eq. of solid sodium triacetoxyborohydride. Sat. aq. NaHCO3 and CH2Cl2 were added after 2 h. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo giving the crude product, which was used without further purification; MS (ES+) m/z 502 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ccc(Cl)cn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(Cl)cn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 45 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-(5-chloropyridin-2-yl)piperidin-4-amine dihydrochloride (0.196 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.124 g, 45%). 1H NMR (500 MHz, CDCl3): δ 8.06-8.02 (m, 1H), 7.55-7.49 (m, 2H), 7.47-7.41 (m, 3H), 7.39-7.33 (m, 1H), 6.52-6.45 (m, 1H), 5.24-5.14 (m, 1H), 4.02-3.93 (m, 1H), 3.18-3.06 (m, 1H), 2.49-2.39 (m, 2H), 1.78-1.66 (m, 2H), 1.72 (s, 9H), 1.39-1.28 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 157.4, 146.3, 137.5, 134.1, 131.9, 130.2, 128.9, 125.3, 120.5, 108.2, 107.3, 61.9, 50.5, 44.3, 32.0, 27.8; Mass Spectrum: M−H+ 475.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][O:7][CH2:16][C:15]([CH3:17])=[CH2:14])[CH3:2]
Reactant: CCOC(CCO)OCC
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)COCCC(OCC)OCC
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a stirred solution of 3,3-diethoxy-1-propanol (3.0 g, 22.2 mmol) in anhydrous THF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 1.07 g, 26.6 mmol). The reaction mixture was stirred for 30 minutes, and 3-bromo-2-methyl-1-propene (3.63 g, 24.5 mmol) then added. The reaction mixture was then stirred for a further 18 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to afford an oil (2.25 g, 50%). The material used in the next step without further purification.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][NH:19][CH2:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[CH2:20][N:19]([CH3:18])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cc2ccccc2o1
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Product: CN(Cc1cc2ccccc2o1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 87.8 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (1.60 g, 6.3 mmole) for the (E)-3-(2-oxo[2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) for the 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g, 90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]([CH3:11])[C:9]2[C:8](=[O:12])[N:7]3[CH2:13][CH2:14][N:15]=[C:6]3[N:5]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:4]=2[N:3]=1.[CH3:24][CH:25]([CH3:28])[CH2:26][NH2:27]>C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]2[C:4]3[N:3]=[C:2]([NH:27][CH2:26][CH:25]([CH3:28])[CH3:24])[N:10]([CH3:11])[C:9]=3[C:8](=[O:12])[N:7]3[CH2:13][CH2:14][N:15]=[C:6]23)=[CH:18][CH:19]=1
Reactant: Cn1c(Br)nc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Reactant: CC(C)CN
Solvent: CCO
Product: CC(C)CNc1nc2c(n1C)C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
A mixture of the product of Procedure 46, 1.0 g. (0.0025 mole) and 0.37 g. (0.005 mole) of 2-methylpropylamine in 20 ml. of ethanol is refluxed for 16 hrs. The desired product precipitated as the hydrobromide salt which was collected and mixed with dilute aqueous sodium hydroxide to convert it into the free base form, m.p. 185°-187°.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)ON1C(=O)C2C3C=CC(C3)C2C1=O

Procedure:
N-Hydroxy-norborn-5-ene-2,3-dicarboximide (17.92 g, 0.1 mole) is largely dissolved in 100 mL chloroform and 21 mL (0.15 moles) triethylamine, followed by adding 19 mL (0.2 moles) acetic anhydride at 0° C. with stirring. After stirring for 2 hours at room temperature, the solvent is largely removed, the residue is mixed with water and the precipitate is filtered off.
Reaction SMILES: [OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[CH3:25][NH2:26]>>[OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([NH:26][CH3:25])=[O:4]
Reactant: CN
Reactant: COC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Product: CNC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Yield: 80 %

Procedure:
A solution of methyl (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)propanoate (2.43 g, 7.5 mmol) in methylamine solution (33% wt. in absolute ethanol, 40 mL) was heated to 75° C. in a sealed tube for 1 hour . The cooled reaction mixture was then concentrated under reduced pressure to afford a yellow syrup. Purification by crystallization from 80% chloroform/hexane (50 mL) afforded 1.93 g (80%) of (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropanamide as a white crystalline solid. MS (ES) m/z 323.2 ([M−H]−); HRMS: calcd for C19H20N2O3+H+, 325.15467; found (ESI, [M+H]+), 325.1562.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:10]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9]3)=[O:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C2(c3ccccc3)CC2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 1-phenylcyclopropanecarboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%. MS M+H calculated 337.6, found 337.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:27]#[C:26][CH2:25][OH:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Product: OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as light brown solid, MS: 343 (MH+, 1Br).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][C:9]([CH:11]([C:32]1[S:33][CH:34]=[C:35]([Cl:37])[N:36]=1)[C:12]1[NH:13][C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:15]2[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[N:17]([CH3:24])[C:16]=12)=[CH2:10])(=O)=O>C1COCC1>[Cl:37][C:35]1[N:36]=[C:32]([CH:11]2[C:12]3[N:13]([C:14]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[N:17]([CH3:24])[C:16]4=3)[CH2:10][C:9]2=[CH2:8])[S:33][CH:34]=1
Reactant: C=C(COS(C)(=O)=O)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1Cn2c(-c3cccc(F)c3)c3c(=O)n(C)c(=O)n(C)c3c2C1c1nc(Cl)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% wt. in mineral oil, 31.2 mg, 0.779 mmol) was added to a solution of 2-((4-chlorothiazol-2-yl) (5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-7-yl)methyl)allyl methanesulfonate (140 mg, 0.260 mmol) in THF (8 mL). The mixture was stirred at room temperature for 2 hours. A further portion of sodium hydride (31.2 mg, 0.779 mmol) was added to allow the reaction to run to completion. The reaction was quenched with water and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.3 %

Procedure:
A mixture of 2-bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (3.57 g, 10.91 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (2.76 g, 10.91 mmol) and potassium carbonate (2.26 g, 16.36 mmol) in anhydrous dimethylformamide (25 mL) was stirred at room temperature for 17 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.27 g): MS: (+) m/z 523.11, 525.04 (M+Na+, 79Br/81Br).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1>>[F:36][C:32]1[CH:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=[CH:34][CH:33]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-bromo-3-fluorobenzene
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:26]1[C:31]2([CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH2:30][NH:29][CH2:28][CH2:27]1.[CH2:44]([C:46]1[S:50][CH:49]=[C:48]([C:51](O)=[O:52])[CH:47]=1)[CH3:45].[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>CN(C=O)C.C1(C)C=CC=CC=1.C(Cl)Cl.C(N(CC)CC)C>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[CH2:44]([C:46]1[S:50][CH:49]=[C:48]([C:51]([N:29]2[CH2:30][C:31]3([CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)[O:26][CH2:27][CH2:28]2)=[O:52])[CH:47]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CCc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (1.15 g) was added in one portion to a solution at 0° C. of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.682 g) and 5-ethylthiophene-3-carboxylic acid (0.364 g) and triethylamine (1.3 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the ‘BOC’ protected intermediate. DCM (10 mL) was added followed by trifluoroacetic acid (10 mL) and the resultant solution allowed to stand at 20° C. for 25 minutes. Toluene (30 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped twice with acetonitrile to yield the subtitled compound. Yield 0.950 g.