Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][C:8]3([C:11]42[NH:15][C:14](=S)[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[NH3:20]>>[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][C:8]3([C:11]42[N:15]=[C:14]([NH2:20])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CCC21CC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Yield: 81.6 %

Procedure:
7′-Bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 12, 0.688 g, 2.05 mmol) in ammonia (7 M in methanol, 18 mL, 126 mmol) was heated in a microwave reactor for 60 min at 100° C. Five times the mixture was concentrated, re-dissolved in ammonia (7 M in methanol, 18 mL, 126 mmol) and microwaved again for 40 to 60 minutes at 100° C. Purification by flash silica gel chromatography using a stepwise gradient of CHCl3/MeOH (30:1-20:1-10:1) gave the title compound (0.532 g, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.00-0.08 (m, 1 H), 0.11 (ddd, 1 H), 0.22 (ddd, 1 H), 0.51 (dt, 1 H), 1.46 (dt, 1 H), 2.17 (s, 3 H), 2.28-2.39 (m, 1 H), 2.82-2.98 (m, 2 H), 6.56 (d, 1 H), 6.58 (br. s., 2 H), 7.12 (d, 1 H), 7.30 (dd, 1 H); MS (ES+) m/z 318.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[O:17][C@H:18]4[CH2:41][N:21]([C:22](=[O:40])[C@H:23]([C:36]([CH3:39])([CH3:38])[CH3:37])[NH:24][C:25](=[O:35])[O:26][C@@H:27]5[CH2:34][C@H:28]5[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:8]=23)[C@H:20]([C:42]([NH:44][C@:45]2([C:50](=[O:59])[NH:51][S:52]([C:55]3([CH3:58])[CH2:57][CH2:56]3)(=[O:54])=[O:53])[CH2:47][C@H:46]2[CH:48]=[CH2:49])=[O:43])[CH2:19]4)[CH2:2]1.[CH2:60]=O.[BH4-].[Na+]>CO>[C:36]([C@H:23]1[C:22](=[O:40])[N:21]2[CH2:41][C@@H:18]([CH2:19][C@H:20]2[C:42]([NH:44][C@:45]2([C:50](=[O:59])[NH:51][S:52]([C:55]3([CH3:58])[CH2:56][CH2:57]3)(=[O:54])=[O:53])[CH2:47][C@H:46]2[CH:48]=[CH2:49])=[O:43])[O:17][C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]([O:6][CH2:5][CH:3]3[CH2:2][N:1]([CH3:60])[CH2:4]3)=[C:8]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[CH2:34][C@H:27]2[O:26][C:25](=[O:35])[NH:24]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCC1CNC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCC1CN(C)C1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the amine from Step 1 (20.6 mg) in methanol (1 mL) was added formaldehyde (10 μl). Sodium borohydride (5.6 mg) was added slowly. The clear reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the product was dissolved in ethyl acetate and water (with acetic acid to a pH=5). The mixture was extracted (3×) with ethyl acetate. The combined organics were dried with sodium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO reverse phase, 0 to 95% water in acetonitrile followed by ISCO: 0 to 20% methanol in DCM) gave the desired product (1.4 mg). LRMS (ES+) m/z 849.55 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:19][C:20]1[C:21](=[O:39])[N:22]([CH2:34][C:35]([O:37]C)=[O:36])[C:23]([CH3:33])=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:33][C:23]1[N:22]([CH2:34][C:35]([OH:37])=[O:36])[C:21](=[O:39])[C:20]([NH:19][S:15]([CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:17])=[O:16])=[C:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(Cc2ccccc2)c(N)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cc2ccccc2)c(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
1 ml (7.17 mmol) of triethylamine and 0.95 g (5 mmol) of (phenylmethyl)sulphonyl chloride are added to 1 g (3.5 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydropyridine-1-acetate in solution in 30 ml of dichloromethane and the mixture is kept stirred for 12 hours at room temperature. The reaction medium is washed successively with 10 ml of water, 10 ml of a 1 N aqueous hydrochloric acid solution and then 10 ml of a saturated sodium chloride solution. The medium is dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. The product is used as such in the hydrolysis stage which is carried out according to the procedure described in Example 3. 0.8 g of product is obtained in the form of a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH:20]1([CH2:23][O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]2[N:29]=[CH:30][C:31]([NH:34][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:32][CH:33]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Reactant: CN(CCOCC1CC1)c1ccc(N)cn1
Product: CN(CCOCC1CC1)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-cyclopropylmethoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C23H22BrF3N4O3 (m/e) 539, obsd 540 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:8]#[C:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC#Cc1ccccn1
Temperature: 4 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 4-(pyridin-2-yl)but-3-yn-1-ol (3.60 g, 24 mmol) in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32 mmol). The mixture was cooled at 4° C. and methanesulfonyl chloride (2.50 mL, 32 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured over ice/water (100 mL) and stirred for 5 min. To this mixture was added saturated aqueous sodium bicarbonate solution (50 mL) chilled to 4° C., and the mixture was stirred for 30 min, then extracted with DCM. The combined organic fractions were dried over MgSO4, filtered and concentrated under pressure to afford 4.60 g of 4-(pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 83%) as a brown oil which can be used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][S:14]([O-:16])=[O:15].[Na+]>CS(C)=O>[CH2:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=1)[CH3:9]
Reactant: CS(=O)[O-]
Reactant: CCc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(S(C)(=O)=O)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-bromo-4-ethyl-5-nitro-pyridine (4.35 mmol) and sodium methanesulfinate (4.35 mmol) in DMSO (10 mL) was stirred at room temperature for 1.5 h. The mixture was poured into ice-water and stirred until the ice had melted. The mixture was filtered and the solid (the desired product) was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](Cl)=O>>[Cl:16][CH2:17][C:18]1[N:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=[CH:10][C:11]2=[N:14][N:15]=1
Reactant: NNc1ccc(-c2cccc(Cl)c2)nn1
Reactant: O=C(Cl)CCl
Product: ClCc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
As for Example 2, 6-(3-chlorophenyl)-3-hydrazinopyridazine is reacted with chloroacetyl chloride to give the product of the Example.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][C:7]1=[O:18]>C(#N)C>[N:1]([C:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][C:7]1=[O:18])=[N+:2]=[N-:3]
Reactant: CCOc1ccc2c(c1)C(Cl)(c1ccccc1Cl)C(=O)N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CCOc1ccc2c(c1)C(N=[N+]=[N-])(c1ccccc1Cl)C(=O)N2
Yield: 66 %

Procedure:
0.339 g of sodium azide is added to a solution of 0.560 g of the compound obtained in step B or B' in 20 ml of acetonitrile and the mixture is refluxed for 30 minutes. The solvent is evaporated off under vacuum and the residue is taken up with water, extracted with AcOEt, washed with a saturated solution of NaCl, with water and with a 5% aqueous solution of sodium dithionite, re-extracted with DCM, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.377 g of the expected product. Infrared spectrum in DCM: 3440 cm-1, 2100 cm-1, 1745 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][CH:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[Br:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(CC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)sc1Br
Reaction time: 4 h
Yield: 40.8 %

Procedure:
5-Ethyl-thiophene-3-carboxylic acid ethyl ester (1.2 g, 6.52 mmol) was dissolved in acetic acid (10 mL). N-Bromosuccinimide (7.1 mmol) was added and the reaction was stirred for 4 hours. The solvent was removed under vacuum and the product purified by flash chromatography on silica, eluting with 0%-30% t-butylmethylether in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.7 g). 1H NMR (400 MHz, CHCl3-d): δ 7.05 (s, 1H), 4.3 (q, 2H), 2.75 (q, 2H), 1.4 (t, 3H), 1.3 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23]C1C=C2C(=CC=1)C(N)CC2>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1ccc2c(c1)CCC2N
Product: CCc1cnc(CC)c(NC2CCc3cc(OC)ccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methoxyindan-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.89, 2.58, 2.67, 2.73, 2.91, 3.00, 3.83, 4.51, 5.69, 6.79, 6.85, 7.26, 7.69; 13C NMR (CDCl3) δ 11.08, 13.97, 26.04, 28.55, 30.84, 35.35, 55.79, 55.87, 110.39, 113.15, 125.21, 130.10, 137.12, 140.93, 145.91, 151.82, 153.69, 160.25; HRMS (FAB) calcd for C18H23N3O+H 298.1919, found 298.1900. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.51; H, 8.00; N, 13.82.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:15])[NH2:14]>C(N(CC)CC)C.CO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][N:13]([CH3:15])[CH3:12])[CH:7]=1
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
10 g (0.0628 mol) of 2,4-difluoronitrobenzene was stirred for 4 days with 4.36 g (0.0728 mol) of N,N-dimethylhydrazine in 7.08 g of triethylamine and 100 ml methanol. The mixture was concentrated and the resulting solid dissolved in methylene chloride, washed with water and brine, dried with MgSO4 and concentrated to yield an orange solid. The solid was triturated in 95% ethanol/water, filtered and dried to give 6.1 g 4-fluoro-2-(2,2-dimethylhydrazino) nitrobenzene, m.p. 67°-71° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:11]([O:13]C)=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1>CO>[CH3:3][O:4][C:5]1[C:6]([C:11]([OH:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ncccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A 5 N sodium hydroxide solution (147 μL) was added to a solution of methyl 3-methoxypyridine-2-carboxylate (112 mg) in methanol (2 mL), and the mixture was stirred at room temperature overnight. The excess of methanol was evaporated under reduced pressure, and the residue was diluted with water. The aqueous layer was washed with ether and then made weak acidic with 5 N hydrochloric acid. The aqueous layer was extracted with a THF-ethyl acetate mixed solvent, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (19 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][CH2:30][CH2:31][S:32]([N:35](C)[CH3:36])(=[O:34])=[O:33]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][CH2:30][CH2:31][S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[N:9]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Reactant: CN(C)S(=O)(=O)CCN
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCS(=O)(=O)NC)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-amino-N,N-dimethylethanesulfonamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH:5]1[CH2:12][CH:11]2[CH:7]([C:8]([OH:25])=[C:9]([C:14]3[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:15]=3[CH2:23][CH3:24])[C:10]2=[O:13])[CH2:6]1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([O:13][C:10]1[CH:11]2[CH:7]([CH2:6][CH:5]([CH:4]=[N:3][O:2][CH3:1])[CH2:12]2)[C:8](=[O:25])[C:9]=1[C:14]1[C:15]([CH2:23][CH3:24])=[CH:16][C:17]([CH3:22])=[CH:18][C:19]=1[CH2:20][CH3:21])=[O:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1cc(C)cc(CC)c1C1=C(O)C2CC(C=NOC)CC2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C)cc(CC)c1C1=C(OC(=O)C(C)(C)C)C2CC(C=NOC)CC2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
0.104 g (0.31 mmol) of 5-(2,6-diethyl-4-methylphenyl)-6-hydroxy-4-oxo-1,2,3,3a,4,6a-hexahydropentalene-2-carbaldehyde O-methyloxime (compound I-a-13 according to the invention), 0.040 g (0.34 mmol) of pivaloyl chloride and 92 mg (0.91 mmol) of triethylamine in 8 ml of dichloromethane are stirred at room temperature for 2 h. The mixture is poured onto ice, taken up in dichloromethane, washed with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. Chromatography on silica gel (mobile phase ethyl acetate/hexane v:v=25:75) gives 107 mg of the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]=1[C:9]([O:11]CC)=O.[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[C:16]([C:15]1[C:14](=[O:21])[NH:1][C:2]2[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]=2[C:9]=1[OH:11])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1=C(N)CCC(C)C1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1c(O)c2c([nH]c1=O)CCC(C)C2

Procedure:
Condensation of ethyl 2-amino-5-methyl-cyclohex-1-ene-1-carboxylate (37 g; 0.202 mole) with diethyl malonate (32.4 g; 0.202 mole) at 110° C as described in Example 1 gave the title compound; m.p. (EtOH) 214° -216° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:37][CH2:38][C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)=[O:40]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3N)[nH]c2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a suspension of methyl 2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (2.44 g, 6.68 mmol), sodium acetate (602 mg, 7.3 mmol) and acetic acid (0.45 ml, 7.86 mmol) in tetrahydrofuran (20 ml) was added dropwise chloroacetyl chloride (0.60 ml, 7.53 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and a mixed solvent of hexane:ethyl acetate (4:1) was added to the residue. The precipitated solid was collected by filtration to give methyl 2-[2-(2-chloroacetylamino)-5-fluorophenyl]-3-cyclohexyl-1H-indole-6-carboxylate (2.5 g, yield 84.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([NH2:21])=[N:18][C:19]=2[NH2:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.O>N1C=CC=CC=1>[C:22]1(=[O:27])[N:21]([C:17]2[N:18]=[C:19]([NH2:20])[C:14]([CH2:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][N:16]=2)[C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(Cc2cnc(N3C(=O)c4ccccc4C3=O)nc2N)cc(OC)c1OC
Reaction time: 2 h
Yield: 55.6 %

Procedure:
8.7 g of trimethoprim are dissolved in 50 ml of pyridine at about 50° C., and then 4.5 g of phthalic anhydride are added. The mixture is stirred for another two hours at from 80° to 90° C.; after cooling, 100 ml of water are added. The precipitate is washed with water and recrystallized from ethanol. 7 g of 2-phthalimido-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 221° C. are obtained as intermediate product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:17]=[C:16]([CH2:18][CH:19]([N:25]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[ClH:44]>C(OCC)(=O)C>[ClH:44].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:17]=[C:16]([CH2:18][CH:19]([NH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:15][N:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1

Procedure:
2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 1.35 mmol) was stirred in a mixture of ethyl acetate (20 mL) and 1N hydrochloric acid (100 mL) for 3 hours. The reaction was neutralized by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with diethyl ether. The combined organics were dried over magnesium sulfate and the solvent removed in vacuo. The resulting oil (200 mg) was used directly in example 14C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:29]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)cc1OC
Yield: 96.9 %

Procedure:
According to the General Procedure F, carbon tetrabromide (4.00 g, 12.05 mmol), triphenylphosphine (6.30 g, 24.10 mmol) and 3,4-Dimethoxybenzaldehyde (2.00 g, 12.05 mmol) are converted to give after workup and chromatography (SiO2, CH2Cl2, Rf=0.48) the title compound (3.76 g, 11.68 mmol, 97%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]O)[CH:5]=[CH:6][CH:7]=1.[BrH:11]>>[Br:11][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Br
Reactant: Nc1cccc(CCO)c1
Product: Nc1cccc(CCBr)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 2-(3-Amino-phenyl)-ethanol (2.0 g) in 48% aq HBr (20 ml) was heated at 90° C. for 18 h. The mixture was cooled to room temperature, and the precipitate formed was collected by filtration. The solid was dried in vacuo yielding Building block M, 1.8 g (61% yield). LCMS purity 90%, m/z 200/202 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[CH2:9][CH2:8]1
Reactant: CN1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CN1CCc2ccc(S(=O)(=O)Cl)cc21
Temperature: 0 °C
Yield: 6.9 %

Procedure:
ClSO3H (400 g, 3.45 mol) was cooled to 0° C. and 1-methylindoline (35 g, 263.16 mmol) was added dropwise with stirring, maintaining the temperature at 0° C. The resulting solution was then warmed to room temperature and stirred for 20 hours. The reaction mixture was added carefully then dropwise to 3 L of iced water and the resulting solution was extracted using dichloromethane (3×400 mL). The organic layers were combined, dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography using a 1:30 ethyl acetate/petroleum ether solvent system. The collected fractions were combined and concentrated to give 4.2 g (7%) of 1-methylindoline-6-sulfonyl chloride as a brown solid. 1H NMR (CDCl3) δ 7.34 (d, 1H), 7.20 (d, 1H), 6.95 (s, 1H), 3.52 (t, 2H), 3.08 (t, 2H), 2.86 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1.F[C:12]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=1[C:14]#[N:15].O>CN(C=O)C>[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][O:10][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[CH:5]=1
Reactant: Cc1cc(CO)no1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccccc2C#N)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of 60% sodium hydride (0.164 g; 4.10 mmol) in DMF (5 mL) at 0° C. was added dropwise (5-methylisoxazol-3-yl)methanol (0.456 g; 4.00 mmol) and stirred at 0° C. for 30 minutes. The mixture was added to a solution of 2,6-difluorobenzonitrile (0.556 g, 4.00 mmol) in DMF (5 mL) at 0° C. and stirred for 18 hours at ambient temperature. The solution was poured into a mixture of ice and water. The solid was collected by filtration and dried in a 40° C. vacuum oven to yield 540 milligrams of (5-methylisoxazole-3-ylmethoxy)benzonitrile.