Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24]([N:25]=1)=[C:23]1[CH2:26][CH:27]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]3)[O:28][C:22]1=[CH:21][N:20]=2.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24]([N:25]=1)=[C:23]1[CH2:26][CH:27]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([NH:36][CH2:12][C:9]4[CH:10]=[CH:11][C:5]5[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:32][CH2:31]3)[O:28][C:22]1=[CH:21][N:20]=2
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](N)CC1)O3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NCc2ccc4c(c2)NC(=O)CO4)CC1)O3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (27 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamine (47 mg, 0.14 mmol, 1.0 eq) in 1,2-dichloroethane (4 mL) and methanol (1 mL), followed by acetic acid (11 μL, 0.19 mmol, 1.3 eq) and sodium cyanoborohydride (11 mg, 0.16 mmol, 1.15 eq). After 5 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-{[trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamino]-methyl}-4H-benzo[1,4]oxazin-3-one as a white lyophilized powder (13 mg, 18% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO.O>[CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of methyl 2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate (0.015 g, 0.04 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4-5 with 10% HCl and extracted with ethyl acetate (2×15 ML). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.011 g, 80%). 1H-NMR (400 MHz, CDCl3) δ 7.86 (d, J=5.6 Hz, 1H), 7.50 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07 (dd, J=13.1, 2.8 Hz, 2H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.56 (m, 2H), 6.32 (d, J=2.0 Hz, 1H), 4.38 (dd, J=14.3, 7.0 Hz, 1H), 4.07 (t, J=5.8 Hz, 2H), 4.01 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (t, J=6.7 Hz, 2H), 2.92 (q, J=7.1 Hz, 1H), 2.08 (m, 2H), 1.12 (d, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C20H23N3O3 354.3 (M+H); Found: 354.2.
Reaction SMILES: C1CCN(CCCN2CC3C4C=CC(F)=CC=4C(NC=3CC2)=O)CC1.[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O:44]C)=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.[OH-].[Li+:59]>>[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O-:44])=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[Li+:59]
Reactant: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)nn2Cc1ccccc1
Agent: O=c1[nH]c2c(c3ccc(F)cc13)CN(CCCN1CCCCC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)nn2Cc1ccccc1
Yield: 100 %

Procedure:
Following general procedure GP-L, (S)-methyl 1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (520 mg, 1.24 mmol) and lithium hydroxide monohydrate (129 mg, 3.07 mmol) were converted lithium (S)-1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (509 mg, quant. yield), which was used in the next step without further purification: MS (ESI+) m/z 405 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]([CH2:24][C:25]3([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]3)[CH2:22][NH2:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([C:18]1[CH:19]=[N:20][C:15]([CH:12]2[CH2:13][CH2:14]2)=[CH:16][CH:17]=1)[CH2:24][C:25]1([C:28]([F:29])([F:30])[F:31])[CH2:27][CH2:26]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=457.1, tR (minutes, Method G)=1.96
Reaction SMILES: [Na].[N:2](OCCC(C)C)=[O:3].O.[CH3:11][C@:12]12[C:20](=[O:21])[CH2:19][C@H:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13]2>C(OCC)C>[OH:3][N:2]=[C:19]1[CH:15]2[C:16]([CH3:17])([CH3:18])[C:12]([CH3:11])([CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: CC(C)CCON=O
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CC12CCC(C(=NO)C1=O)C2(C)C

Procedure:
In 600 ml of dried diethyl ether was dissolved 130 g (0.854 mol) of commercially available D-camphor, and 20.4 g of metallic sodium was added thereto. The solution was kept at 0° C. with stirring, and 123 ml (0.916 mol) of isoamyl nitrite was added thereto to conduct a reaction for 14 hours. After completion of the reaction, 200 ml of water was added to the reaction mixture, and the aqueous layer was separated. To the aqueous layer was added 400 ml of 10% hydrochloric acid, and the solid thus formed was extracted with diethyl ether. The ether layer was dried and concentrated to obtain 51 g of 3-hydroxyiminocamphor.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14](=[O:52])[CH2:15][N:16]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19](=[O:33])[C@H:18]([CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37](C(OC(C)(C)C)=O)[N:36]=4)[C:17]3=[O:51])[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][C@@H:18]2[C:17](=[O:51])[N:16]([CH2:15][C:14]([N:13]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:52])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]2=[O:33])=[N:36]1
Reactant: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 1.25 h

Procedure:
A solution of tert-butyl 3-({(3R)-1-[2-(6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate (93 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). Stirred for 1.25 hours and concentrated the solvent off. Chromatographed on silica gel (Hexane:Ethyl Acetate) then lyophilized to yield the title compound as a white film (64 mg).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C>>[C:1]12([CH2:7][C:8](=[O:10])[O:14][C:12](=[O:13])[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)O1
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of 1,1-cyclohexanediacetic acid (39.95 mmol) in acetic anhydride (159.8 mmol) was refluxed gently until a clear solution was obtained (ca. 1 h). The reaction mixture was kept at reflux for another hour until the reaction was complete. The reaction mixture was cooled to room temperature and acetic acid and excess acetic anhydride were removed under vacuum to afford 7.28 g (100%) of (3). 1H NMR (CDCl3): 2.65 (4H, s); 1.54-1.43 (10H, m).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13].[H-].[Na+].[C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)(OCC)=[O:17].C(O)C>N1C=CC=CC=1>[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][S:6][CH2:5][CH2:4][NH:3][C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)=[O:17]
Reactant: CCOC(=O)Nc1nc(C)cs1
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1csc(NC(=O)NCCSCc2nc[nH]c2C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To 3.40 g (13.9 mmole) of 4-[(2-aminoethyl)thiomethyl]-5-methylimidazole dihydrochloride stirred under flowing nitrogen in 100 ml of dry pyridine is added 1.27 g (ca. 27.9 mmole) of a 50 percent dispersion in oil of sodium hydride. After approximately 90 min. 24.3 g (13.1 mmole) of 2-carbethoxyamino-4-methylthiazole is added, and the resultant mixture is heated at reflux for 1 day. After cooling to room temperature, the mixture is filtered to remove insolubles, and the filtrate is concentrated at reduced pressure. The resultant gum is repeatedly dissolved in aqueous ethanol and dried in vacuo, triturated with pentane to remove mineral oil, and purified by column chromotography* on silica gel. Fractions containing the product are combined, partially concentrated, filtered and finally dried by concentration in vacuo, giving 2.40 g (7.2 mmole) of the desired product as an ethanol solvate. Structure assignment and solvation by one-half mole of ethanol per mole of product are supported by nmr.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[CH:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:12].C(NC(=O)[O-])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[Br:12][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][CH:11]=[CH:10]2
Reactant: C#Cc1cc(C#N)cc(Br)c1N
Agent: CC(C)(C)NC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a mixture of 4-amino-3-bromo-5-ethynylbenzonitrile (0.57 g) and 1-methyl-2-pyrrolidinone (12 mL) was added tert-butylcarbamate (0.57 g) under ice-cooling, followed by stirring at room temperature for 24 hours. To the reaction mixture was added a 10% aqueous citric acid solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 7-bromo-1H-indole-5-carbonitrile (0.55 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](N(OC)C)=[O:20]>C1COCC1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9])=[O:20]
Reactant: CON(C)C(=O)CCCCl
Reactant: Fc1ccc(F)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(CCCCl)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[H][H]>O1CCCC1.CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: [H][H]
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1C(N)CC2
Yield: 97 %

Procedure:
A mixture of 7-methoxy-indan-1-one oxime (CAS 908108-58-7, (E)-oxime 179899-16-2) (22.3 g, 126 mmol)) and Raney-Nickel (11.26 g) in tetrahydrofuran (570 mL) and methanol (570 mL) was hydrogenated at 100 bar hydrogen-pressure at 60° C. for 22 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles were removed in vacuum to give the title compound as a brown oil (19.95 g, 97%, HPLC 0.4 min), MS (ISP) m/e=164.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:25]1([NH:31][N:32]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=2)[C:3]2[CH:21]=[CH:22][CH:23]=[N:24][C:2]=2[Cl:1])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=NNc2ccccc2)c2cccnc2Cl)cc(C(C)(C)C)c1O

Procedure:
A solution of 7 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol and 2.4 g of phenylhydrazine in 40 ml of pyridine is refluxed for 7 hours. After the pyridine is distilled off under reduced pressure, to the residue is added water and the precipitated crystals are washed with water to give crude crystals of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol phenylhydrazone, melting at 181° C. with decomposition in an almost quantitative amount.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1)c1ccccc1
Reaction time: 2 h
Yield: 19.5 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (0.86 g, 4 mmol) was dissolved in dry tetrahydrofuran (20 ml) under an atmosphere of argon. Triethylamine (0.61 g, 6 mmol) was added, followed by benzoyl chloride (0.62 g, 4.4 mmol). The mixture was then stirred for 2 hours. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated in vacuo. The orange oil obtained was purified by MPLC, eluting with dichloromethane/ethyl acetate (9:1 v/v) to give (4-benzamidophenylsulphonyl)nitromethane (0.25 g, 20% yield) as a solid, m.p. 211°-212° C.; microanalysis, found: C, 52.3; H, 3.7; N, 8.4%; C14H12N2O5S requires: C, 52.5; H, 3.75; N, 8.75%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: c1c[nH]nn1
Reactant: CC(=O)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(F)ccc1-n1nccn1
Temperature: 140 °C
Reaction time: 4.5 h
Yield: 26.6 %

Procedure:
1-(2,5-Difluorophenyl)ethanone (3.00 g) and 1H-triazole (1.99 g) were dissolved in N-methylpyrrolidone (5 ml). To the solution, potassium carbonate (2.66 g) was added, and the mixture was stirred at 140° C. for 4.5 hours. After standing to cool, water and ethyl acetate were added to the reaction solution to separate the aqueous and organic layers. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, washed three times with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.05 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[S:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.Cl>[CH:1]1([C:7]2[C:8]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[S:18][C:9]=3[N:10]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2cc(C(=O)O)sc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution (0.5 M) of ethyl 4-cyclohexyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in DMF was treated with NaH (2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min, then 2-chloro-N,N-dimethylacetamide (3 eq.) was added. The reaction mixture was heated at 50° C. for 1 h and 25 min. After cooling down, it was diluted with AcOEt and aqueous HCl (1 M) was added. The aqueous phase was separated and extracted with AcOEt. The combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and evaporated. The residue was dissolved in THF/MeOH (1:1). The resulting solution (0.07 M) was treated with NaOH (2 N, 6 eq.). The reaction mixture was heated to reflux overnight. After cooling down, the reaction was concentrated and acidified to pH 1 with aqueous HCl (3 N). The resulting mixture was diluted with DMSO and purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; linear from 95% A to 5% A in 10 min) to afford the title compound (27%) as a solid.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccco1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccco1
Temperature: 100 °C
Reaction time: 9 h
Yield: 97 %

Procedure:
A mixture of 2-acetylfuran (25.0 g, 0.227 mol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After cooling as it was, the reaction mixture was concentrated. To the residue were added diethyl ether and hexane. The resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH3:10])[N:3]=1.Br[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1O
Reactant: FC(F)(F)c1ccccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1OCCCOc1ccccc1C(F)(F)F
Yield: 23.4 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 12, using 2.4 grams (0.010 mole) of 2,4-diamino-5-hydroxy-6-methylpyrimidine hydrosulfate salt (prepared in Steps A-C of this Example), 3.0 grams (0.011 mole) of 2-trifluoromethylphenyl 3-bromopropyl ether, and 8.3 grams (0.060 mole) of finely ground potassium carbonate in 50 mL of N,N-dimethylformamide. The product was recrystallized from methanol and water, yielding 0.8 gram of 2,4-diamino-5-[3-(2-trifluoromethylphenoxy)propoxy]-6-methylpyrimidine, mp 132°-134° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2CCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenethylpyrazin-2-amine (7r) (403 mg, 994 μmol) and 4-(dimethylamino)pyridine (19.6 mg, 160 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11r (298 mg, 455 μmol, 45.8%) as a yellow oily substance. Rf=0.44 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) 0.12 (s, 6H), 0.20 (s, 6H), 0.91 (s, 9H), 0.93 (s, 9H), 2.83 (t, 1H, J=8.4 Hz), 2.94 (t, 1H, J=8.4 Hz), 3.59 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.92-7.00 (AA′BB′, 2H), 7.01-7.07 (AA′BB′, 2H), 7.07-7.15 (m, 1H), 7.16-7.24 (m, 4H), 7.97-8.05 (AA′BB′, 2H), 8.81 (s, 1H), 10.44 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) 8-4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 32.8, 34.7, 41.7, 119.6 (2C), 120.3 (2C), 125.7, 128.1 (2C), 128.2 (4C), 128.5, 129.1, 130.2 (2C), 130.3, 136.6, 141.4, 143.8, 147.9, 150.6, 153.8, 156.6, 170.3; IR (KBr, cm−1) 525, 698, 781, 839, 914, 1007, 1169, 1258, 1362, 1416, 1443, 1510, 1605, 1661, 2857, 2930, 2955, 3225.