Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:28][CH2:27][N:26]([CH:33]4[CH2:34][O:31][CH2:32]4)[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCNC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCN(C4COC4)C3)c2c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of [2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine (21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and oxetan-3-one (7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6 μL, 0.15 mmol). After the mixture being stirred at 55° C. for 1 hour, sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added to the mixture. After being stirred for 2 hours at 65° C., the reaction mixture was concentrated in vacuo. The residue was portioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The separated organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 8.30 (d, J=1.9 Hz, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.78 (s, 1 H), 7.68-7.64 (t, J=3.7 Hz, 1 H), 7.53-7.49 (t, J=3.7 Hz, 2 H), 7.39 (d, J=1.7 Hz, 1 H), 5.98 (s, 1 H), 5.20 (s, 2 H), 4.83-4.78 (m, J=4.7 Hz, 2 H), 4.69-4.60 (m, J=8.4 Hz, 2 H), 4.55 (brs, 2 H), 4.37 (s, 1 H), 3.80-3.74 (m, J=4.1 Hz, 1 H), 3.65-3.61 (m, J=4.2 Hz, 2 H), 2.96-2.89 (m, J=6.6 Hz, 2 H), 2.75-2.72 (m, J=3.3 Hz, 1 H), 2.63-2.47 (m, J=15.9 Hz, 2 H), 2.45 (s, 3 H), 1.95 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]1>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][CH:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reaction time: 0.17 h

Procedure:
To 4-amino-3-methoxybenzoic acid (1.064 g mg, 6.37 mmol) in dichloromethane (50 ml) was added DIPEA (2.22 ul, 12.74 mmol) and TBTU (2.25 g, 7.0 mmol) and the mixture stirred for 10 minutes. 4-amino-1-methylpiperidine (0.872 g, 7.65 mmol) was added and stirring continued for 16 hours. The resulting solid was filtered and dried under vacuum (1.04 g, 3.95 mmol, 62%).
Reaction SMILES: [F-].[K+].[C:3]([C:7]1[C:8](=[O:18])[C:9](=[O:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C([Si](CC)(CC)[C:26]([F:29])([F:28])[F:27])C>C(#N)C>[C:13]([C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:8](=[O:18])[C:9]([OH:17])([C:26]([F:29])([F:28])[F:27])[CH:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(O)(C(F)(F)F)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A mixture of 100 mg (1.7 mmol) of potassium fluoride, 132 mg (0.60 mmol) of 3,5-di-tert-butyl-1,2-benzoquinone, and 2 mL of acetonitrile was treated successively with 40 μL (0.70 mmol) of glacal acetic acid and 129 mg (0.70 mmol) of triethyltrifloromethylsilane, and stirred vigorously at room temperature for 15 minutes. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 20% dichloromethane--80% petroleum ether) to give 27 mg (16% yield) of 4,6-di-tert-butyl-2-hydroxy-2-trifluoromethyl-3,5-cyclohexadiene-one.
Reaction SMILES: [CH3:1][C:2]([CH3:54])([CH2:7][CH2:8][C:9](=[O:53])[N:10]([CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:47])[NH:19][C:20]2[S:21][C:22]3[CH2:46][CH2:45][CH2:44][CH2:43][C:23]=3[C:24]=2[C:25](=[O:42])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4].[CH2:55]=O>>[CH3:54][C:2]([CH3:1])([CH2:7][CH2:8][C:9]([N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:47])[NH:19][C:20]2[S:21][C:22]3[CH2:46][CH2:45][CH2:44][CH2:43][C:23]=3[C:24]=2[C:25](=[O:42])[NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:55])[CH2:40][CH2:41]3)=[CH:31][CH:32]=2)[CH:13]=1)[CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:53])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCN4CCNCC4)cc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Reactant: C=O
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCN4CCN(C)CC4)cc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC

Procedure:
By using 180 mg of methyl 2,2-dimethyl-5-oxo-5-[pentan-3-yl(3-{[3-({4-[3-(piperazin-1-yl)propyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)amino]pentanoate and 0.06 mL of a 37% aqueous formalin solution, the reaction similar to Preparation Example 14 was performed, thereby obtaining 152 mg of methyl 2,2-dimethyl-5-[(3-{[3-({4-[3-(4-methylpiperazin-1-yl)propyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)(pentan-3-yl)amino]-5-oxopentanoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27]C)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCCC)CC4)=CC=3)=CN=2)=CC=1)#N.C(C1C=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCC)CC4)=CC=3)=CN=2)=CC=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:11][N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Agent: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Agent: CCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Product: C[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1

Procedure:
2-(4'-cyanophenyl)-5-[4'-(trans-4"-ethylcyclohexyl) phenyl] pyrimidine ##STR29## 2-(4'-cyanophenyl)-5-[4'-(trans-4"-butylcyclohexyl) phenyl] pyrimidine ##STR30## 2-(4'-cyanophenyl)-5-[4'-(trans-4"-pentylcyclohexyl) phenyl] pyrimidine ##STR31## 2-(4'-cyanophenyl)-5-[4'-(trans-4"-hexylcyclohexyl) phenyl] pyrimidine 2-(4'-cyanophenyl)-5-[4'-(trans-4"-heptylcyclohexyl) phenyl] pyrimidine
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:10])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].O>CS(C)=O>[CH2:22]([N:8]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCCCCCCCCBr
Reactant: O=C1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCN1C(=O)CCCC1=O
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
This example illustrates a synthesis of N-(11,10-Oxidoundecyl)glutarimide (inventive compound no. 1611). Sodium hydride (95%) (168 mg, 7 mmol) was added to a solution of glutarimide (565.6 mg, 5 mmol) in dimethyl sulfoxide (15 mL). After 20 minutes of stirring, 1-bromundec-10-ene (1.165 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichlormethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% ethyl acetate/hexane eluant to yield 0.777 g (58.6% yield) N-(10-Undecenyl)glutarimide (inventive compound no. 1610).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)cc1
Yield: 78.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 4-methoxyphenyl isocyanate (0.016 g, 14.2 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 4 (0.037 g, 0.086 mmol, 78%) as a white solid. LCMS m/z (%)=431 (M+H79Br, 89), 433 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.02 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].[I-].[K+].Cl>CCOCC.CN(C=O)C>[ClH:39].[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1OCC(CCN2CCC(Cc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 4 from 0.3 g of 4-benzylpiperidine, 0.8 g of the compound obtained in step C of EXAMPLE 4, 0.24 g of potassium iodide and 5 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.13 g of the expected product. M.p.=124° C.
Reaction SMILES: [C:1]([C:4]([CH3:39])([CH3:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([N:21](C(OCC(C)C)=O)[C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].C[O-].[Na+]>CO>[C:1]([C:4]([CH3:39])([CH3:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)(C)C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)(C)C(=O)O)cc1
Yield: 42.7 %

Procedure:
2-[4-(2-carboxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (334 mg) was dissolved in methanol (10 ml) and sodium methoxide (324 mg) was added. The solution was heated to reflux for 4 hours, cooled and evaporated to dryness. The residue was partitioned between water (20 ml) and ethyl acetate (15 ml) and the organic layer was separated and washed with water (20 ml). The combined aqueous phases were acidified with 2M hydrochloric acid and extracted with ethyl acetate (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was triturated with isohexane to give 2-[4-(2-carboxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (117 mg); 1H NMR (d6-DMSO): 1.1 (s, 6H), 2.24 (s, 3H), 2.85 (br, 2H), 3.80 (s, 3H); 7.13 (br, 2H), 7.35 (br d, 2H), 7.50 (br s, 1H), 7.57 (q, 1H), 8.78 (dd, 1H), 10.41 (br s, 1H); mass spectrum (+ve ESP) 457.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:30][C:29]([CH:31]=O)=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][C:29]2[S:30][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:23])[CH3:24])[CH:14]=4)=[N:10][C:9]=3[CH:28]=2)[CH2:36][CH2:35]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sc(C=O)cc3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(Cc2cc3nc(-c4cccc(O[SiH2]C(C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Reaction time: 72 h
Yield: 88 %

Procedure:
A mixture of 4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine-6-carbaldehyde (6.67 g, 14.66 mmol), N-methylpiperazine (2.11 mL, 1.3 equivalents) and acetic acid (838 μL, 1.0 eq.) was stirred in 1,2-dichloroethane (70 mL) at room temperature. To this was added sodium triacetoxyborohydride (3.42 g, 1.1 equivalents) and the reaction mixture was stirred for 3 days. The reaction mixture was then quenched with aqueous sodium bicarbonate solution, extracted exhaustively with chloroform, dried (MgSO4), and the solvent removed in vacuo to yield a yellow oil. This was purified using flash chromatography (silica, ethyl acetate to ethyl acetate/methanol) to yield 6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (6.95 g, 88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Product: C[C@@H](O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 22.3 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.086 g, 0.32 mmol) was reacted with (R)-1-(4-aminophenyl)propan-2-ol (0.058 g, 0.38 mmol) to afford the title compound (0.027 g, 22%) as a light yellow solid. MW=378.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m, 5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:15][CH:14]=1
Reactant: NO
Reactant: N#Cc1ccc(Oc2ccccn2)cc1
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C

Procedure:
4-(Pyridin-2-yloxy)benzonitrile (701 mg, 3.57 mmol) was dissolved in ethanol (14.0 mL), and hydroxylamine (472 mg, 14.3 mmol) was added and the mixture was refluxed for 16 hours. The reaction was cooled to room temperature and then concentrated in vacuo to give the product as a yellow syrup and was taken to the next step without further purification (818 mg, 100%). 1H NMR (500 MHz, CDCL3) δ(ppm): 4.91 (2H, bs), 6.94 (1H, dt, J=8.4, 0.8 Hz), 7.02 (1H, ddd, J=7.2, 5.0, 0.8 Hz), 7.16 (2H, d, J=8.6 Hz), 7.66 (2H, d, J=8.6 Hz), 7.71 (1H, ddd, J=8.2, 7.2, 2.0 Hz), 8.21 (1H, ddd, J=5.0, 2.0, 0.8 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 112.1 (CH), 119.1 (CH), 121.4 (CH), 127.6 (CH), 129.0, 139.8 (CH), 147.9 (CH), 152.4, 155.8, 163.4. MS (FAB+): 230 (MH+). HRMS for C12H11N3O2 (MH+): calculated: 230.0930; found 230.0934.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:12](Br)=[CH:11][N:10]=[C:9]([S:14][CH3:15])[N:8]=1)=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(Cl)Cl>[CH3:3][C:2]1[C:12]2[CH:11]=[N:10][C:9]([S:14][CH3:15])=[N:8][C:7]=2[C:5](=[O:6])[NH:4][CH:1]=1
Reactant: C=CCNC(=O)c1nc(SC)ncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CSc1ncc2c(C)c[nH]c(=O)c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of N-allyl-5-bromo-2-(methylthio)pyrimidine-4-carboxamide (Preparation 187, 24 mg, 0.083 mmol), diisopropylethyl amine (60 μl, 0.344 mmol) and PdCl2dppf.DCM (7 mg, 8.57 μmol) was dissolved in DMA (0.8 mL) and heated to 120° C. for 18 hours. Additional batches of base (60 uL) and catalyst (7 mg) were added and the mixture stirred at 150° C. for 8 hours. The mixture was diluted with DCM and quenched with brine. The aqueous layer was extracted with DCM and the combined organic layers washed with water, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 5% MeOH in DCM to give the title compound (8 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]1=2>C(O)C.[Pd].Cl>[CH2:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:21])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCCCc1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of 13.8 g of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-1-hexanone (from Example 1.1) in 200 ml ethanol abs., containing 2 g of palladium on carbon 10% and 3 drops of HCl 25%, was subjected to H2 atmosphere for 3 hours (until consumption of theoretical amount H2 is reached and thin layer chromatography showed no more starting material was present). The mixture was filtered and concentrated in vacuo. The residue was diluted in 200 ml ether, dried over MgSO4, filtered and concentrated in vacuo, giving a yellow oil. The crude product was distilled under vacuum (T=120° C. at 0.08 bar), yielding a pale yellow oil (12.1 g). B.p. 120° C. at 0.08 bar.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.OC1C=CC(C(O)=O)=CC=1.O>Br>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN([C@H](C)c3ccc(Br)cc3)CC2)cc1
Agent: Br
Agent: O=C(O)c1ccc(O)cc1
Solvent: O
Product: C[C@H](c1ccc(Br)cc1)N1CCNCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(R)-1-(1-(4-Bromophenyl)ethyl)-4-tosylpiperazine (4.44 g, 10.49 mmol) and 4-hydroxybenzoic acid (4.35 g, 31.46 mmol) in hydrobromic acid (33% in AcOH, 40 mL,) were stirred at room temperature for 48 hours. Water (40 mL) was then added to the dark mixture and stirring continued for a further 2 hours to give a beige solid, which was filtered off and washed with water (10 mL). The combined filtrate and washings were washed with toluene (3×50 mL) then cooled to 5° C. and basified to pH>10 with 40% NaOH. The resulting mixture was extracted with tert butyl methyl ether (2×50 mL) and the combined extracts washed with saturated brine, dried over MgSO4 and evaporated to give (R)-1-[1-(4-bromophenyl)ethyl]piperazine (2.69 g, 95%) as an orange, viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1.C1(C)C=CC=CC=1.N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCC(n2cncn2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1
Temperature: 25 °C

Procedure:
5-cyclohex-1-enyl-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (555 mg, 1.436 mmol) was treated with a 1M solution of trans-4-methylcyclohexanecarbonyl chloride in toluene (2.87 mL, 2.87 mmol). Pyridine (128 μl, 1.58 mmol) was added and the mixture was stirred at reflux overnight under nitrogen. It was cooled to room temperature and dilute with EtOAc. The resulting mixture was washed twice with a saturated aqueous sodium bicarbonate and once with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a gradient from 50% EtOAc:hexanes to 100% EtOAc as eluent to afford 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (494 mg, 67%) as a yellow mixture of cis and trans isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1>[Ni].CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1
Reactant: CCCCCC(O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Agent: [Ni]
Solvent: CO
Product: CCCCCC(O)CCC1CCC(CCCCCCCC(=O)OC)O1
Yield: 94.8 %

Procedure:
IV (1.77 g, 0.00500 mole), methanol (50 ml), and Raney nickel (1 g) were shaken under hydrogen at a pressure of 70 atmospheres for 24 hours at room temperature. After filtration, the solvent was removed from a water bath (60° C, 10 mm Hg). Ether (50 ml) was added to the residue, and the turbid, colourless solution was filtered. The ethereal solution was evaporated to dryness from a water bath (60° C, 10 mm Hg). The residual clear, colourless oil (1.90 g) was distilled under reduced pressure to give 1.69 g (95%) of VI as a colourless oil, b0.05 160°-172° C, nD25 1.4625.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([N:4]2[C:8]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnnn2C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(c2nnnn2C2CC2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound from Step B above (200 mg, 0.68 mmol) was dissolved in 4 M HCl in dioxane (4.0 mL) and stirred at RT for 1 h. The product was concentrated under reduced pressure and dried under high vacuum to the title compound (i-37) (127 mg, 96%). ESI-MS calculated for C9H15N5: Exact Mass: 193.13. Found 194.14.