Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.N.[H][H]>CO.[Ni]>[CH3:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(C)cc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2c(c1)C(N)CCO2
Yield: 61.3 %

Procedure:
A solution of the product of Example 7A (4.24 g) in 50 mL of a mixture of 20% ammonia in methanol was treated with 40 g Raney Nickle under 60 psi hydrogen for 4 hours at ambient temperature. The reaction mixture was filtered, and the solvent evaporated under reduced pressure. The residue was taken in diethyl ether, washed sequentially with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated to give 2.22 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.11 (s, 1H), 6.95 (d, 1H, J=8.5 Hz), 6.71 (d, 1H, J=8.5 Hz), 4.22 (m, 2H), 4.01 (m, 1H), 2.27 (s, 3H), 2.10-2.21 (m, 1H), 1.78-1.88 (m, 1H). MS (DCI) m/e 164 (M+H)+.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[CH3:9][NH:10][CH2:11][CH:12]=[CH2:13]>>[CH2:11]([N:10]([C:3]1([C:1]#[CH:2])[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:9])[CH:12]=[CH2:13]
Reactant: C#CC1(O)CCCC1
Reactant: C=CCNC
Product: C#CC1(N(C)CC=C)CCCC1

Procedure:
In analogy to example 37.5 and 37.6, 1-Ethinylcyclopentanol and N-Methyl-allylamine were converted to yield Allyl-(1-ethynyl-cyclopentyl)-methyl-amine as colorless oil, MS: 163 (M).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]([CH2:17][OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[N:24]=[CH:23][N:22]([C:25](N2C=NC=C2)=[O:26])[CH:21]=1>C(Cl)Cl>[N:22]1([C:25]([O:18][CH2:17][C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:26])[CH:21]=[CH:20][N:24]=[CH:23]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CCC[C@@H](CO)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)CCC[C@@H](COC(=O)n1ccnc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-hydroxyhexanoate (4.4 g, 16 mmol) in DCM (50 mL) was added CDI (3.1 g, 19 mmol). The reaction was complete in 30 min. DCM was removed. The residue was purified on silica gel column (hexanes/EtOAc 1:1) to give (S)-2-(tert-butoxycarbonyl(methyl)amino)-6-methoxy-6-oxohexyl 1H-imidazole-1-carboxylate (5.1 g, 85%) as a colorless oil. LRMS (M+Na+) m/z 392.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9]1[CH:14]=[C:13](F)[C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1F
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1-n1ccnc1
Yield: 87.1 %

Procedure:
By using 3.77 g (12.1 mmol) of N-(4-acetyl-5-fluoro-2-nitrophenyl)glycine tert-butyl ester, 3.28 g of imidazole and 15 ml of DMF, 3.80 g (87%) of N-[4-acetyl-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine tert-butyl ester was obtained.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]([CH3:34])[C:16]([C:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=1)=[O:17])[CH:8]=[CH:7]2>C(O)(=O)C.C(OCC)(=O)C.C(O)(C)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][N:15]([CH3:34])[C:16]([C:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:19]=1)=[O:17])=[CH:10]2
Reactant: CN(Cc1ccc2cc(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: BrBr
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 215.1 %

Procedure:
A solution of bromine (0.37 mL, 0.7134 mmol) in 60 mL glacial acetic acid was added dropwise under nitrogen over 2 h to a solution of 1-benzyl-1H-indole-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.0 g, 0.713 mmol), prepared in the previous step, in 300 mL glacial acetic acid at room temperature. The reaction stirred for 18 h (overnight). The solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate and extracted with 5% sodium bicarbonate. A solid precipitated from the organic layer and was collected by filtration. The filtrate was dried (MgSO4) and concentrated under reduced pressure to give a tan solid. The two solids were combined and taken up in a mixture of ethyl acetate and isopropanol. A certain amount of material (1.0 g) would not dissolve upon heating and was removed by filtration. The filtrate was allowed to cool and upon cooling crystals formed. The crystals were collected by filtration and dried under reduced pressure to give 1-benzyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.766 g, 22%) as a tan solid, mp 181-182° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCO.CCOC(C)=O.[Pt]=O>[NH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:38])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Yield: 60.4 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{2-[(3-nitrobenzyl)oxy]ethoxy}hexyl)-1,3-oxazolidin-2-one (0.10 g) in EtOH (3 ml) and EtOAc (3 ml) was hydrogenated for 19.5 h over platinum oxide (0.020 g). The mixture was filtered through celite, and the solvent evaporated in vacuo to give a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (8:2) followed by solvent evaporation in vacuo gave the title compound (0.057 g). LCMS RT=3.43 min, ES+ve 499 (MH)+.
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.Cl[C:32]([O:34][CH2:35][CH2:36][F:37])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:32]([O:34][CH2:35][CH2:36][F:37])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: O=C(Cl)OCCF
Product: CCO[C@H]1CN(C(=O)OCCF)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 2-fluoroethyl chloroformate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34–7.26, 5.21, 4.70–4.58, 4.56, 4.42, 4.34, 4.10, 3.99, 3.75–3.30, 2.71, 2.47, 1.32–1.26, 1.15; IR (liq.) 2973 (s), 2347 (b), 2181 (w), 1709 (s), 1567 (s), 1553 (s), 1500 (s), 1470 (s), 1445 (s), 1426 (s), 1396 (s), 1347 (s), 1140 (s), 1103 (s), 1060 (s), cm−1 HRMS (FAB) calcd for C23H29Cl2FN4O3+H 499.1679, found 499.1673. Anal. Calcd for C23H29Cl2FN4O3: C, 55.32; H, 5.85; N, 11.22. Found: C, 55.20; H, 5.91; N, 10.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.CN1CCOCC1.C(N)CCCCC>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:32][CH2:36][CH2:35][CH2:40][CH2:39][CH2:38][CH3:37])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: F[B-](F)(F)F
Solvent: CCCCCCN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCCCNC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 16.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.050 g, 0.127 mmol), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.082 g, 0.225 mmol), N-methyl morpholine (0.025 g, 0.247 mmol), DMF (0.5 mL), THF (3.0 mL) and n-hexyl amine (0.026 g, 0.257 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 0.86 (s, 3H), 1.23 (s, 3H), 1.28 (m, 8H), 1.49 (s, 3H), 3.01 (s, 2H), 7.32-7.33 (m, 2H), 7.21 (s, 1H), 7.69 (s, 1H), 8.43 (s, 2H), 10.91 (s, 1H), 11.39 (s, 1H); MS [M+H]+: 476.33.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]2[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=2[N:23]=1>CN(C=O)C.CCOC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:21][C:22]2[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=3[N:23]=2)[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A suspension of 1-isopropyl-1,3-dihydro-benzoimidazol-2-one (0.79 g, 4.5 mmol) and Cs2CO3 (4.40 g, 13.5 mmol) in DMF (50 mL) was stirred for 30 minutes then 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (1.34 g, 4.5 mmol) was added and the mixture stirred for 5 h at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was evaporated to dryness and the residue taken up in EtOAc (100 mL), washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, hexanes:EtOAc 3:1 to 1:1) to give 1.71 g (95%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([NH:10][C:11]3[C:16]([S:17]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=12.C(OCC)C>CN(C=O)C>[C:1]([N:10]1[C:9]2[C:18](=[CH:19][C:6]([OH:5])=[C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (2 ml) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1) (2.65 gm) in DMF (10 ml) and stirred for 30 minutes. Diethyl ether (100 ml) was added to the reaction mixture followed by ice-water (50 ml). The aqueous layer was decanted and the organic layer containing a solid was evaporated to dryness. The resulting residue was treated with acetone and filtered to afford the title compound.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([C:21](OCC)=[O:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2.C1COCC1.Cl>O>[CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH2:21][OH:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)c1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Yield: 81.6 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added ethyl acenaphtho[1,2-b]quinoline-10-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.75 g, 23 mmol and dry THF (400 mL). The mixture was stirred at reflux for 3 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, passed through a small plug of SiO2 using CH2Cl2 as the eluting solvent. The appropriate fractions were combined and the volume reduced to 100 mL and diluted to 400 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 5.52 g (81.6% yield) of acenaphtho[1,2-b]quinoline-10-methanol, mp 215°-218° was obtained which analyzed correctly (C,H,N) for the assigned structure.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[N:17]=[C:16]([CH:18]=[C:19]5[NH:24][C:22](=[CH:23][C:3](=[N:4]2)[CH2:2]1)[CH:21]=[CH:20]5)[CH2:15][CH2:14]4)=[CH:9][CH:8]=3.O>>[CH2:9]1[C:10]2=[CH:12][C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:24]=[C:22]([CH:23]=[C:3]5[NH:4][C:5](=[CH:6][C:7](=[N:11]2)[CH2:8]1)[CH:1]=[CH:2]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3
Reactant: c1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)CC5)[nH]4)CC3
Solvent: O
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)CC4)[nH]3

Procedure:
Method B (from 16): Following the procedure described for the preparation of 6, treatment of 16 (40.0 mg, 0.0705 mmol, 1.0 equiv) with FeCl36.H2O (66.3 mg, 4.0 equiv) resulted in the desired product. Purification was done by flash column chromatography (silica gel, 3% acetone in CH2Cl2). Yield: 25.2 mg, 55%. 1H NMR (400 MHz, CDCl3) δ: 9.18 (s, 1H, 10-H), 9.03 (d, J=14 Hz, 1H, 5-H), 8.65 (s, 1H, 20-H), 5.79-5.86 (m, 1H, 31-H), 5.48 (d, 2H, 132-H), 4.41-4.50 (m, 1H, 8-H), 4.20-4.22 (m, 1H, 7-H), 3.90 (t, J=8.0 Hz, 2H, 17-CH2), 3.75 (s, 3H, COOCH3), 3.52-3.66 (m, 5H, 31-OCH2+12-CH3), 3.43 (d, J=3.6 Hz, 3H, 2-CH3), 3.23 (s, 3H, 18-CH3), 2.94 (t, J=8.0 Hz, 2H, 171-CH2), 2.42-2.52 (m, 1H, 81-H), 2.13-2.20 (m, 1H, 81-H), 2.10 (d, J=6.8 Hz, 3H, 31-CH3), 1.91/1.87 (d, J=7.2 Hz, 3H, 7-CH3), 1.66-1.76 (m, 3H, 31-OCH2CH2CH2CH2CH2CH3), 1.15-1.23 (m, 9H, 31-OCH2CH2CH2CH2CH2CH3+81-CH3), 0.78-0.81 (m, 3H, 31-OCH2CH2CH2CH2CH2CH3), −0.34 (br s, 1H, NH), −1.52 (br s, 1H, NH). MS (ESI) m/z: 651.4 (M++1). UV-vis, CH2Cl2, λmax nm (ε): 669 (4.45×104), 612 (6.77×103), 540 (6.77×103), 513 (1.11×104), 411 (7.82×104).
Reaction SMILES: Cl.[CH2:2]([NH:9][C@@H:10]([C@@H:14]1[CH2:18][S:17][C:16](=[O:19])[N:15]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11](=[O:13])N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:15]1[C@H:14]2[CH2:18][S:17][C:11](=[O:13])[C@H:10]2[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)[C@@H](NCc1ccccc1)[C@@H]1CSC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.541 g of (4R)-4-[(1S)-1-(N-benzylamino)-1-carbamoylmethyl]-3-benzylthiazolidin-2-one hydrochloride, the solution was stirred under nitrogen atmosphere at 100° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with water, and saturated brine, dried and concentrated. The residue was crystallized from hexane to give 342 mg of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione as colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: NCCCO
Product: N#Cc1cnc2cnc(NCCCO)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-aminopropan-1-ol. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.048 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 3.3 (d, J=6.3 Hz, 4 H) 3.5 (m, 2 H) 6.9 (m, 1 H) 7.0 (s, 1 H) 7.4 (m, 1 H) 7.5 (t, J=9.2 Hz, 1 H) 7.6 (m, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]3=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:11]3[N:10]=[C:9]([C:20]3[CH:21]=[N:22][C:23]([NH:30]C(=O)C(C)(C)C)=[CH:24][C:25]=3[C:26]([F:29])([F:28])[F:27])[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].C(O)(=O)C>C(O)C>[NH2:30][C:23]1[N:22]=[CH:21][C:20]([C:9]2[N:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:12]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:11]3[N:10]=2)=[C:25]([C:26]([F:29])([F:28])[F:27])[CH:24]=1
Reactant: COC(=O)c1cc2c(N3CCOCC3)nc(-c3cnc(NC(=O)C(C)(C)C)cc3C(F)(F)F)nn2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cn1

Procedure:
Compound 22a (300 mg, 0.59 mmol) was suspended in 10 mL of ethanol. 1.5 mL of 2 M potassium hydroxide solution was added and refluxed for 1 hour. The reaction is substantially completed. 2 mL of acetic acid was added. Most of the solvent was distilled off under reduced pressure to precipitate solids. The precipitated solids were filtered to give compound 23a. White solid (224 mg, 92.6%). m.p. 244-245° C. 1H NMR (300 MHz, DMSO-d6): δ 12.54 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.34 (s, 1H), 6.83 (s, 3H), 4.00 (t, J=4.0 Hz, 4H), 3.73 (t, J=4.0 Hz, 4H). LC-MS: 409 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=1.Cl[CH2:32][CH:33]=O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:32]=[CH:33][N:21]=3)[C:15]=2[CH:14]=1
Reactant: O=CCCl
Reactant: COc1ccc2c(c1)c(-c1cc3nc(N)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nccn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Yield: 96.8 %

Procedure:
In a round flask was added 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-amine (0.065 g, 0.15 mmol) and 2-chloroacetaldehyde (˜50 wt % solution in water, 0.030 mL, 0.23 mmol) in EtOH (2 mL) and mixture was heated to about 80° C. for about 45 min. The mixture was concentrated under reduced pressure to give 2-(5-methoxy-1-methyl-1H-indol-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.065 g, 95%): LC/MS (Table 2, b) Rt=1.79 min; MS m/z 448 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Pt]=O>[N:1]1([CH2:6][CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccnc1CN1CCCC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OC1CCCNC1CN1CCCC1
Reaction time: 24 h

Procedure:
A mixture of 2-(pyrrolidinylmethyl)-3-pyridinol (21.0 g) and platinum oxide (1.0 g) in glacial acetic acid (120 ml) was hydrogenated a 70 psi and room temperature for 20 h. Further platinum oxide (1.0 g) was then added and hydrogenation continued at 70 psi for a further 24 h. The reaction mixture was filtered, the combined filtrates were concentrated in vacuo and the residue was dissolved in water (200 ml). This solution was acidified to pH1 with 5M hydrochloric acid before washing with dichloromethane (2×70 ml). The aqueous layer was then basified (pH14) with 5M aqueous sodium hydroxide before extracting with dichloromethane (3×70 ml). The combined extracts were washed with 2M aqueous sodium hydroxide (50 ml) and water (50 ml), dried and concentrated in vacuo to give an oil. This crude product was distilled at reduced pressure (Kughelrohr oven, 140°, 0.8 mm Hg) to give the title compound as a waxy solid, (6.17 g) m.p. 45°-50°.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.NS(O)(=O)=O.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>O.C(O)(C)C.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[F:15][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH:28]=[CH:27][C:26]([O:30][CH3:31])=[O:29])[CH:14]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: NS(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C=Cc1cc(F)ccc1C(=O)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
At 0C, a solution of 0.52 g of sodium nitrite in 1 ml of water is added within a period of 30 minutes to a mixture of 1 g of 2-amino-4-fluorobenzoic acid, 15 ml of water and 6.24 ml of concentrated sulfuric acid. The mixture is then stirred for one hour. Following addition of 0.3 g of amidosulfonic acid, 0.7 g of methyl acrylate in 9 ml of isopropanol are added dropwise, and 10 mg of palladium acetylacetonate are added. After 4 hours at 40° C., 30 ml of water are added and the resulting precipitate is filtered off. Drying gives 1.1 g of 4-fluoro-2-(3-methoxy-3-oxo-1-propenyl)-benzoic acid of melting point 151-153° C.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:34]([N:36]([CH2:42][CH3:43])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:35]>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH2:42][CH3:43])[CH2:34][CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(CC)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NC[C@]4(O)CCC[C@H](C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-diethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 3H), 0.83 (d, 3H). m/z: 474 [M+H]