Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.[Cl-].[NH4+].[Cl-].[Li+]>[C:1]1([C:7]([C:8]2[NH:33][N:32]=[N:31][N:9]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(CCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C2CCN(CCC(c3ccccc3)(c3ccccc3)c3nnn[nH]3)CC2)cc1

Procedure:
11.0 Parts of 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile are dissolved in 55 parts by volume of dimethylformamide along with 2.82 parts of sodium azide, 2.32 parts of ammonium chloride and 0.04 parts of lithium chloride. This mixture is heated under a nitrogen atmosphere, in an oil bath which is kept at 125° C. The solution is cooled and poured into water which caused the formation of a gummy precipitate. The solvent phase is decanted from the gum. The gum is then crystallized from a mixture of methanol-ether and dried in vacuum to provide an off-white solid which is recrystallized from a mixture of methanol-ether and again dried in vacuum to provide 5-[1,1-diphenyl-3-(4-phenylpiperidino)propyl]-1H-tetrazole hemimethanolate, melting at 149° - 157° C. and having the following formula ##STR8##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6]([NH:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49].C(N(CC)CC)C>ClCCl>[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH:49][C:8]([C:7]1[C:6]([NH:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:5][CH:4]=[C:3]([Cl:2])[CH:11]=1)=[O:9]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
To a suspension of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-nicotinic acid hydrochloride salt (0.060 g, 0.12 mmol) in dichloromethane (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.18 mmol). The reaction was stirred at ambient temperature for 5 minutes. This was followed by addition of solution of glycine methyl ester hydrochloride (0.015 g, 0.12 mmol) and triethylamine (0.016 mL, 0.12 mmol) in dichloromethane (0.5 mL). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.030 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][OH:19])[CH2:9][O:10][CH:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].C1(C=CC(O)=CC=1)O.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:12]([F:15])([F:14])[F:13])[C@H:16]1[CH2:17][O:19][NH:18]2
Reactant: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: Fc1ccccc1[C@]12CO[C@H](C(F)(F)F)[C@H]1CON2
Temperature: 128 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone oxime (1.085 kg, 3.328 mol) in xylenes (6.9 L) was added hydroquinone (86.2 g, 0.8 mol) at rt. The solution was heated to 128° C. (internal temperature) for 18 h. The solution was cooled to rt, and hexanes (7.0 L) was added, followed by 4.0 M aq. HCl (2.4 L). The reaction mixture was stirred for 1 h, and filtered. To the solid was added water (2.0 L), methyl tert-butyl ether (7.0 L) and 25% wt. aq. NaOH (0.4 L). The aq. layer was extracted once with methyl tert-butyl ether (7.0 L), the organics were combined, washed with 27% aq. NaCl (2.0 L) and concentrated under vacuum to a black oil (512.0 g, 56%). 1H NMR (500 MHz, CDCl3) δ ppm 7.64-7.52 (m, 1H), 7.39-7.31 (m, 1H), 7.19 (td, J=7.7, 1.2 Hz, 1H), 7.11 (ddd, J=11.9, 8.2, 1.0 Hz, 1H), 4.54 (d, J=10.1 Hz, 1H), 4.34-4.23 (m, 1H), 4.26-4.17 (m, 1H), 4.16 (d, J=10.2 Hz, 1H), 4.10 (d, J=8.5 Hz, 1H), 3.71 (d, J=20.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 160.59 (d, JCF=247.0 Hz), 130.50 (d, JCF=8.7 Hz), 128.72, 124.69 (d, JCF=3.3 Hz), 124.45 (q, JCF=281.8 Hz), 124.43 (d, JCF=11.9 Hz), 116.66 (d, JCF=22.7 Hz), 83.70 (q, JCF=32.1 Hz), 78.17 (d, JCF=3.1 Hz), 77.63. 54.53.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[S:14].C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+].Cl>C(OCC)(=O)C.C(COC)OC.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13]([OH:15])=[S:14]
Reactant: O=C(CCCCCC(C(O)=S)c1ccccc1)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: OC(=S)C(CCCCCC(O)c1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3.61 g. of 8-(2-furyl)-8-oxo-2-phenylthiooctanoic acid, 5.45 ml. of 1M aqueous sodium carbonate, 25 ml. of water and 15 ml. of glyme is added 0.41 g. of sodium borohydride in portions during one minute. The resulting mixture is stirred at ambient temperature for 3.5 hours, diluted with ethyl acetate and acidified cautiously at 0°-10° C. with dilute hydrochloric acid. The organic layer is washed with water and brine, dried and evaporated, giving 3.54 g. of the product as an oil identified by its PMR δ 4.800 (1, t, J=7).
Reaction SMILES: [C:1]1([S:7]([O:9][Na])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N.Cl>O>[C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O[Na])c1ccccc1
Agent: Cl
Agent: N#N
Solvent: O
Product: O=S(O)c1ccccc1

Procedure:
PhSO2Na (1.6579 g., 0.0101 mol) was dissolved in water (100 mL), while keeping an atmosphere of N2. HCl (12M, 0.84 mL, 0.0101 mol) was added in order to produce PhSO2H. Benzoquinone (0.01 mol, 1.081 g) was added while flushing with N2. A white to grey precipitate was formed immediately. The solution was stirred for 5 min, filtered (glass sinter no. 3) under N2, washed with distilled water (-20 mL) and dried under vacuum (+20° C. over night. Yield 2.08 g. The product was identified by 1H- and 13CNMR spectroscopy.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([CH2:12][CH2:13][CH2:14][Cl:15])[O:19][CH2:18][CH2:17][O:16]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc(C2(CCCCl)OCCO2)cc1

Procedure:
This compound was synthesized as described under 5.a) with 20.0 g (83.8 mmol) of 1-(4-tert-butylphenyl)-4-chloro-1-butanone (origin: Acros), 16 ml of ethylene glycol and ca. 1 g of p-toluenesulfonic acid in 120 ml of toluene for 16 h to give 24.1 g (99%) of the crude compound, which was used for further functionalization. Column chromatography of 3 g (SiO2, heptane/ether 4:1) afforded 2.48 g of a slightly yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:30][CH2:31][CH3:32])=[C:6]([CH:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:4]1[C:5]([O:30][CH2:31][CH3:32])=[C:6]([CH:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:13][OH:14])[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
Tert-Butyl (1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)carbamate (500 mg, 1.0 mmol) (from Step 7) was stirred in tetrahydrofuran (10 mL) and a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.5 mL) was added. The mixture was stirred at rt for 30 minutes and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound 238 mg, 60%. LCMS calculated for C17H23ClFNO5Na (M+Na)+: m/z=398.1; found: 398.1.
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Cl-].[Cl:22]C1C=CC(C[Zn+])=CC=1>>[ClH:22].[Cl:1][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[N:11]=[CH:10][C:9]3[C:12]([CH3:15])([CH3:16])[CH2:13][NH:14][C:8]=3[CH:7]=2)=[CH:3][CH:20]=1
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Reactant: Clc1ccc(C[Zn+])cc1
Agent: Cl
Agent: [Cl-]
Product: CC1(C)CNc2cc(Cc3ccc(Cl)cc3)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 4-chlorobenzylzinc chloride instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=273.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([O:10]C)=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].ClC1C=CC(OC)=C(OC)C=1.C(Cl)(=O)C1C=CC=CC=1.II.N1C=CC=CC=1OC(=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:6]1[C:5]([OH:10])=[CH:4][C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1cc(Cl)c(C(=O)c2ccccc2)cc1OC
Agent: COc1ccc(Cl)cc1OC
Agent: II
Agent: O=C(Oc1ccccn1)c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1cc(O)c(O)cc1Cl

Procedure:
The afore-mentioned dihydroxyketone can also be obtained in two stages analogously to Example 9(a) and (b). The (2-chloro-4,5-dimethoxyphenyl)-phenylmethanone required for this purpose can be obtained by acylating 4-chloro-1,2-dimethoxybenzene with benzoyl chloride in the presence of iodine. It is easier to obtain, however, if one equivalent of 4-chloro-1,2-dimethoxybenzene is heated in a bomb tube at 150° for 2 hours with 1.1 equivalents of (2-pyridinyl)-benzoate in trifluoroacetic acid. After working up and demethylation in a manner analogous to Example 9(b), the desired (4,5-dihydroxy-2-chlorophenyl)phenylmethanone is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:19]=[C:20]([C:23]3[NH:27][C:26]([C:28]#[N:29])=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:4]=2[NH:3]1.I[CH3:31]>>[CH3:31][N:27]1[C:23]([C:20]2[CH:21]=[CH:22][C:4]3[NH:3][C:2](=[O:1])[CH2:8][O:7][C:6]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)[C:5]=3[CH:19]=2)=[CH:24][CH:25]=[C:26]1[C:28]#[N:29]
Reactant: CI
Reactant: N#Cc1ccc(-c2ccc3c(c2)C(c2cccs2)(c2cccs2)OCC(=O)N3)[nH]1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(c1cccs1)(c1cccs1)OCC(=O)N2

Procedure:
Prepared from 5-(2-oxo-5,5-dithien-2-yl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.33 (s, 1H), 7.63 (dd, J=5.0, 1.1 Hz, 2H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.03 (m, 4H), 6.89 (dd, J=3.6, 1.1 Hz, 2H), 6.18 (d, J=4.0 Hz, 1H), 4.25 (s, 2H), 3.49 (s, 3H); MS (ES) m/z 432 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3](=[O:33])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH:7]=1.[BH4-].[Na+]>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[C:6]([O:5][CH2:4][CH:3]([OH:33])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:7][C:8]([C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[N:9]1
Reactant: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC(O)C(C)(C)C)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.1 mmol) of (S)-3-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-3-o-tolyl-propionic acid were dissolved in 5 ml of DCM and 0.05 mmol of sodium borohydride were added. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue subjected to preparative HPLC to given 52% of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17]CC2C=CC=CC=2)[C:6]1=[O:25])(=[O:3])[CH3:2].C1(C)C=CC=CC=1>[Pd]>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Temperature: 45 °C
Reaction time: 15.5 h

Procedure:
To a solution of (3R)-1-((1R,2R)-2-benzyloxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (3a) in toluene (446 g, 0.151 mol) was added 10% Pd/C (6.3 g, 50 wt-% water wet), and the reaction vessel was flushed twice with H2. The reaction mixture was agitated at 18° C. under H2 (5 bar) for 8 hours and at 45° C. under H2 (5 bar) for 15.5 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered, the filtrate was washed with toluene and the filtrate was concentrated in vacuo to give 3-(R)-1-[(1R,2R)-2-hydroxycyclohexyl]-2,5-dioxopyrrolidin-3-yl acetate (4a) as a white hygroscopic foam (46.0 g).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2ncccn12
Yield: 37.1 %

Procedure:
6-(3-Methyl-imidazo[1,2-a]pyrimidin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.1 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) and 2-aminopyrimidine (2.9 g). mp. 288°-290° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:38](Cl)(Cl)=[S:39].O>C(Cl)Cl.N1C=CC=CC=1>[OH:28][CH:17]([CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][O:19][C:20]1[C:21]2[NH:27][C:38](=[S:39])[NH:26][C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Reactant: S=C(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: OC(COc1cccc2[nH]c(=S)[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
[3-(N,N-Dibenzylamino)-2hydroxypropoxy]-2,3-diamino benzene (400 mg, 1.1 mmol) was dissolved in a mixture of methylene chloride (70 mL) and pyridine (35mL) and cooled to DOC. Dimethylamino pyridine (DMAP; 311mg, 2.5mmol) was added and thiophosgene (179mg, 0.119mL, 1.6mmol) was introduced in a dropwise fashion. After 30 minutes, another equivalent of thiophosgene was added and the mixture was stirred for 5 hours. Water was carefully added and the resulting biphasic mixture extracted with methylene chloride. The organic solution was dried over MgSO4 and, filtered and evaporated to leave a brown oil (445mg, ca. 100%). MS, NMR.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnc(NC2CC2)nc1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc(NC2CC2)nc1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine (as prepared above) and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp: 136-137° C.; 1H NMR (300 MHz, CDCl3) δ: 8.40 (2H, s), 8.21 (1H, s), 7.96-7.99 (1H, d, J=9.0 Hz), 7.52-7.55 (1H, d, J=9.0 Hz), 7.49-7.52 (1H, d, J=9.0 Hz), 7.23-7.26 (1H, d, J=9.0 Hz), 7.15-7.18 (1H, d, J=9.0 Hz), 5.81 (1H, s), 5.28 (1H, s), 3.57 (2H, s), 2.78 (1H, s), 2.55 (8H, brs), 2.46 (3H, s), 2.32 (3H, s), 0.83-0.87 (2H, m), 0.56 (2H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H32N7: 478.2714. found: 478.2718.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([N:20]([O:21][CH3:22])[CH3:19])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 38.2 %

Procedure:
3-(N,N-diethylaminosulfonyl)benzoic acid (1.17 g, 4.55 mmol) and N,O-dimethylhydroxylamine hydrochloride (498 mg, 5.11 mmol) were dissolved in CH2Cl2 (30 mL). To this solution was added triethylamine (1.9 mL, 14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (970 mg, 5.06 mmol) and 4-(N,N-dimethylamino)pyridine (117 mg, 0.958 mmol). The resulting solution was stirred at room temperature for 17 h then poured into saturated aqueous NaHCO3 and extracted 3× with ethyl acetate. The combined organics were washed with brine then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 70:30 hexanes:acetone) to yield 522 mg of the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH3:9][C:10]([CH3:12])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH:10]([N:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1)([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: N#CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-cyanopiperidine (5.8 g, 53 mmol, J. Org. Chem. 21, 984-986, 1957) in methanol (30 mL) and THF (130 mL) was added with stirring acetone (7.7 mL) and glacial acetic acid (6.0 mL) followed by portionwise addition of sodium cyanoborohydride (6.6 g, 105 mmol). When addition was complete the mixture was stirred overnight at ambient temperature. The solvent was evaporated and to the residue was added 1N hydrochloric (110 mL) until pH 1. The mixture was washed with diethyl ether (100 mL) and the acidic aqueous phase was saturated with potassium carbonate. The alkaline mixture (pH 10) was extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 8.2 g of 1-isopropyl-4-cyanopiperidine. 1H NMR 400 MHz, DMSO-d6) δ 0.96 (d, 6H), 1.63-1.73 (m, 2H), 1.80-1.92 (m, 2H), 2.35-2.44 (m, 2H), 2.58-2.67 (m, 2H), 2.69-2.78 (m, 1H), 2.79-2.87 (m, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17]C(=O)C)[C:11]=1[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][OH:17])[C:11]=1[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccnc(CO)c1C
Yield: 82.3 %

Procedure:
17.3 g (0.059 mol, 1.0 eq.) of 4-octyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 25% aqueous solution of sodium hydroxide at 11 to 22° C., and the mixture was allowed to react for one hour at room temperature, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and then concentrated to dryness, to obtain 12.2 g of 4-octyloxy-2-hydroxymethyl-3-methylpyridine as a pale brown oily matter (yield 82.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([CH2:20][C:13]3[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=3[F:11])[C:22]([NH2:23])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2ccc(Cl)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-chlorobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile.
Reaction SMILES: C[O:2][C:3]1[C:12](=O)[N:11]([CH3:14])[C:10]2[N:9]=[CH:8][N:7]=[C:6]([N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C:5]=2[N:4]=1.[OH2:32].[OH-].[Li+].Cl>O>[CH3:14][N:11]1[C:12]([C:3]([OH:32])=[O:2])=[N:4][C:5]2[C:10]1=[N:9][CH:8]=[N:7][C:6]=2[N:15]1[CH2:31][CH2:30][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][NH:20][C:19]2=[O:29])[CH2:17][CH2:16]1
Reactant: COc1nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc2n(C)c1=O
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(C(=O)O)nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc21
Temperature: 60 °C
Reaction time: 48 h

Procedure:
6-Methoxy-8-methyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)pteridin-7(8H)-one (1 g, 2.37 mmol) was treated with lithium hydroxide monohydrate (0.281 g, 4.74 mmol) tetrahydrofuran (2.5 mL) and water (2.5 mL). This mixture was stirred at 60° C. for 48 hours. The reaction mixture was cool to room temperature acidified to pH 4 with 1 M hydrochloric acid (8 mL) and evaporated under reduced pressure. The resulting crude material was then used in the next step without any further purification. MS (EI) for C20H21N7O3: 408 (MH+), 364 (MH+−44 (—CO2)).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH:4]1[CH:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([O:3][C:9]([C:6]1[CH:7]=[CH:8][NH:4][CH:5]=1)=[O:10])[CH3:2]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc[nH]c1
Temperature: 60 °C
Yield: 79.8 %

Procedure:
Ethanol (3.2 mL, 54 mmol) and 4-dimethylamino pyridine (DMAP) (54 mg, 0.45 mmol) were added to a mixture of pyrrole-3-carboxylic acid (500 mg, 4.5 mmol) and dicyclohexylcarbodiimide (1.11 g, 5.4 mmol) (Aldrich, Milwaukee, Wis.) in tetrahydrofuran (THF) (15 mL). After heating at 60° C. for 10 hours, the reaction was cooled. The precipitate was filtered off, washed with ethyl acetate, the combined filtrate was concentrated and purified on a silica gel column to give 500 mg (81%) of 1H-pyrrole-3-carboxylic acid ethyl ester as a colorless oil.