Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]4=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2c(C)nn3C)c1
Product: COc1cccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2c(C)nn3C)c1

Procedure:
(6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxyphenyl)-amine was reacted with indazole boronic acid pinacol ester using General Procedure A to give 141. NMR (CDCl3): 2.78 (3H, s), 3.89 (3H, s), 4.14 (3H, s), 6.79 (1H, dd), 7.02 (1H, br. s), 7.25 (1H, m), 7.37 (1H, t), 7.54 (1H, t), 7.63-7.68 (2H, m), 8.45 (1H, d), 9.10 (1H, s), 10.11 (1H, br). MS: MH+ 386.20 (100%)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:22]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25].CC#N>CCOC(C)=O>[CH2:22]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC1CCNCC1
Reactant: O=c1ccc2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 60 h
Yield: 49 %

Procedure:
A 7 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.450 g, 2.0 mmol), K2CO3 (0.34 g, 2.5 mmol), KI (0.42 g, 2.5 mmol), 4-butylpiperidine (0.30 g, 2.1 mmol) and dry CH3CN (3 mL). The mixture was shaken at 50° C. for 60 h and thereafter diluted with EtOAc (50 mL) and washed with water (50 mL). The water phase was extracted with EtOAc (2×50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.32 g, 49%). 1H NMR (CD3OD) δ 7.88 (d, J=9.6 Hz), 7.68 (brd, J=8.0 Hz), 7.65-7.61 (m, 2H), 7.33-7.25 (m, 1H), 6.64 (d, 9.6 Hz), 4.39-4.32 (m, 2H), 2.95-2.86 (m, 2H), 2.50-2.43 (m, 2H), 2.01-1.86 (m, 4H), 1.71-1.62 (m, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.6 Hz); 13C NMR (CD3OD) δ 163.1, 140.4, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.7, 22.8, 13.2.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=O)(C)(C)C.I[CH3:22].[H-].[Na+]>CN(C=O)C>[CH3:20][C:9]1([CH3:19])[CH:10]([CH3:22])[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.1 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2 H), 6.60 (t, J=7.3, 1 H), 6.45 (d, J=7.3, 1 H), 3.61 (br s, 1 H), 2.74 (dd, J=16.6, 5.3, 1 H), 2.47 (dd, J=16.6, 10.3, 1 H), 1.82 (m, 1 H), 1.20 (s, 3 H), 1.05 (s, 3 H), 0.97 (d, J=7.2, 3 H).
Reaction SMILES: [NH2-:1].[Li+].N.[Li].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16](OC)=[O:17])=[C:10]2[O:20][CH:21]([CH3:23])[CH3:22]>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH2:1])=[O:17])=[C:10]2[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1[nH]c2ccc(OC)cc2c1OC(C)C
Reactant: [NH2-]
Agent: N
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Lithium amide in liquid ammonia is prepared as described by Unangst PC and Carethers ME, J. Heterocyclic Chem. 1984;21:709, from lithium metal ribbon (0.059 g, 8.5 mmol). A solution of methyl 5-methoxy-3-(1-methylethoxy)-1H-indole-2-carboxylate (0.15 g, 0.57 mmol; Unangst PC, et al., J, Heterocyclic Chem. 1987;24:811) in 4.0 mL of tetrahydrofuran is added dropwise. The mixture is stirred for 1 hour and the excess ammonia is allowed to evaporate. The residue is diluted with ethyl acetate, and the organic layer is washed with 1.0N HCl brine, saturated sodium bicarbonate solution, and brine again. The solution is dried (anhydrous magnesium sulfate) and evaporated. Recrystallization of the residue from ethyl acetatehexane gives 0.11 g (76%) of product; mp 138.5°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:10].[N+:11]([O-:14])(O)=[O:12].[OH-].[Na+].[C:17](O)(=[O:19])[CH3:18]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N+:11]([O-:14])=[O:12])[C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][C:4]=1[CH3:10]
Reactant: COc1ncc(N)cc1C
Reactant: CC(=O)O
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1nc([N+](=O)[O-])c(NC(C)=O)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous acetic acid (20 ml) was added to 6-methoxy-5-methyl-3-pyridineamine (1.18 g, 8.54 mmol) under ice cooling, and stirred at 0° C. for 20 minutes and at room temperature further for 1 hour. The reaction mixture was cooled at 0° C. again, fuming nitric acid (2 ml) was dropped thereto, and the mixture was stirred at 0° C. for 1 hour and 55 minutes and at room temperature further for 1 hour and 45 minutes. The reaction mixture was poured onto ice and adjusted to pH 9 with a 5N sodium hydroxide solution, extracted with ethyl acetate, and then the solvent was evaporated, thereby yielding the title compound (1.94 g) as a yellow solid crude product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][CH2:12][N:13]([CH2:24][CH2:25]Cl)S(C1C=CC(C)=CC=1)(=O)=O.[CH:27]1(B(O)O)[CH2:29][CH2:28]1>>[CH:27]1([C:2]2[CH:8]=[CH:7][C:5]([N:6]3[CH2:11][CH2:12][NH:13][CH2:24][CH2:25]3)=[C:4]([CH3:9])[CH:3]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Br)ccc1N
Reactant: OB(O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Product: Cc1cc(C2CC2)ccc1N1CCNCC1
Yield: 35.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 15 and using 4-bromo-2-methylaniline (3 g), N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (5.65 g) and cyclopropylboronic acid (721 mg), 1-(4-cyclopropyl-2-methylphenyl)piperazine (640 mg) was obtained. To a solution (7 mL) of 6-bromonicotinic acid (132 mg) in methanol were added 1-(4-cyclopropyl-2-methylphenyl)piperazine (150 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (217 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (260 mg).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Br.[OH:23][C:24]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([OH:34])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: Oc1ccc2c(c1O)CCNC2
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Agent: Br
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(O)c4O)C3)c3ccccc3n2)c1
Yield: 9 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide gave compound 48 (9% yield) as brown oil. 1H NMR (300 MHz, CD3OD) δ 2.83 and 3.05 (2t, 2H), 3.55 and 4.14 (2t, 2H), 3.87-3.92 (2s, 3H), 4.40 and 4.98 (2s, 2H), 6.15 and 6.64 (2d, 1H), 6.54 and 6.75 (2d, 1H), 7.08-7.12 (m, 1H), 7.41-7.47 (m, 1H), 7.69-7.74 (m, 1H), 7.88-8.21 (m, 5H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])[CH2:25][CH2:24]2>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:27]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Product: COc1ccc2c(c1)CCC(c1ccccc1NCCc1ccc(OCc3ccccc3)cc1)C2
Yield: 36.4 %

Procedure:
Synthesized from 4-benzyloxyphenylacetyl chloride (2.3 g) and 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.5 g) according to an analogous synthetic method to Example 152, the title compound (1.0 g) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C@H:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:2]1.[CH3:14][C:15]1[S:24][C:23]2[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N:19]=[C:18](N)[C:17]=2[CH:16]=1.C1(C)C=CC=CC=1.CS(C)=O>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C@@H:8]2[NH:9][CH2:10][CH2:11][N:12]([C:18]3[C:17]4[CH:16]=[C:15]([CH3:14])[S:24][C:23]=4[NH:22][C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[N:19]=3)[CH2:13]2)=[CH:2]1
Reactant: c1cc(CC[C@H]2CNCCN2)co1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccoc2)C1
Temperature: 100 °C
Reaction time: 48 h
Yield: 23.6 %

Procedure:
Combine (S)-2-(2-furan-3-yl-ethyl)-piperazine (550 mg, 3.05 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (700 mg, 3.05 mmol), toluene (6 mL) and DMSO (1.5 mL). Heat at 100° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate. Filter the solids and dilute the filtrate with water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 282 mg (24%) of the title compound: mass spectrum (ion spray): m/z=393 (M+1), 391 (M-1). HR-MS calculated for C22H25N4OS: 393.1749. Found 393.1742. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:28])[C:13]4[CH:14]=[N:15][N:16]([S:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[Cl:38][CH2:39][C:40]1[N:45]=[C:44]([C:46](Cl)=[O:47])[CH:43]=[CH:42][CH:41]=1.O>C(Cl)(Cl)Cl>[Cl:38][CH2:39][C:40]1[N:45]=[C:44]([C:46]([NH:28][C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:47])[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1cccc(CCl)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To solution of 6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amine (1.37 g) in chloroform (30 ml) at 0° C. was added DIPEA (1.232 ml). 6-(Chloromethyl)-2-pyridinecarbonyl chloride (1.519 g, crude) in chloroform (15 ml) was added dropwise and the mixture was stirred at 0° C. for 15 min. Water (30 ml) was added and the mixture was extracted with DCM (50 ml), separating the layers by hydrophobic frit.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([CH:34]([CH3:37])[C:35]#[CH:36])[CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH:34]([CH3:37])[C:35]#[C:36][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)N(CC)CCO
Product: CCN(CCO)C(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol were converted to yield 2-(Ethyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol as brown oil, MS: 419 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:18]([O-])=O)[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].ClC1C=C2C(=C(N)C=1OCC1CC1)NC1C=NC=CC2=1.C(O)=O>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: [H][H]
Reactant: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Solvent: CO
Solvent: O=CO
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-7-ethoxy-8-nitro-9H-β-carboline (160 mg, 0.55 mmol) was suspended in 4 ml of methanol and 25 mg of Pd/C (10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained and determined to be the desired 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine (80 mg, 55%). 1H-NMR (300 MHz, Methanol-d4/CDCl3): δ 1.26 (t, 3H), 3.91 (q, 2H), 7.34 (s, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.56 (s, 1H). Retention Time (LC, method: formic acid standard): 1.16 min. MS (M+H+): 262.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].Br[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=1[C:23]([O:25][CH3:26])=[O:24].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: OCCCCNc1ccc2ccccc2n1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1c(C)cccc1COCCCCNc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(Quinolin-2-ylamino)-butan-1-ol (432 mg, 2.0 mmol, EXAMPLE 42a) is dissolved in 20% DMPU in THF (5 mL) and cooled to 0° C. Sodium hydride (60%, 88 mg, 2.2 mmol) is added portionwise, and the contents are stirred for 10 min. Methyl 2-bromomethyl-6-methyl-benzoate (77%, 631 mg, 2.0 mmol, EXAMPLE 2a) is added and the contents are allowed to warm to r.t. and continue to stir overnight. The reaction contents are poured into water (100 mL) and extracted with ethyl acetate (3×75 mL). Sodium chloride is added to the aqueous layer on the second and third extractions. The organic fractions are pooled, washed with brine (2×150 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to give the title compound. MS (ESI) 379 (M+H)+.
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:17]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18].C(OCC)C.S(Cl)([Cl:39])=O>>[N:1]#[N:2].[ClH:39].[CH:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:17]([NH:20][C@H:21]([C:29]([Cl:39])=[O:31])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O
Agent: N#N
Solvent: CCOCC
Product: Cl
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3 g of N2 -(2-phenoxathiinylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([NH:8]C(=O)OC(C)(C)C)[CH2:3]1.FC(F)(F)S(O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)[N:33]=3)[CH:30]=2)[N:25]=[CH:24][CH:23]=1)(=O)=O.CCN(C(C)C)C(C)C>CC(O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]5[S:39][CH:40]=[CH:41][N:42]=5)[N:33]=4)[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:5][C@@H:4]([NH2:8])[CH2:3]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Oc1ccnc2ccc(-c3cccc(-c4nccs4)n3)cc12)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)C1
Yield: 51 %

Procedure:
A solution of tert-butyl (3S,5R)-5-methylpiperidin-3-ylcarbamate (1.5 equiv.) and 6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl trifluoromethanesulfonate (1.0 equiv.) and DIEA (2.0 equiv.) in i-PrOH was heated in a microwave at 150° C. (5×20 min). Upon cooling the material was purified directly by RP-HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (3S,5R)-5-methyl-1-(6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl)piperidin-3-amine (51%). LC/MS=402.0 (M+H), LC=2.16 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[CH:9][CH:8]=1>C1COCC1.C(OCC)(=O)C>[C:7]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:9][C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1
Reactant: O=CNc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
LAH (96 mg, 2.5 mmol) was added portionwise to a cold (at 0° C.) solution of N-biphenyl-4-yl-formamide (100 mg, 0.5 mmol) in THF (2 mL) and the stirring was continued at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was quenched with 3% aq NaOH solution, the precipitate obtained was filtered, the filtrate was collected was concentrated under reduced pressure to get a residue. The residue was diluted with ethyl acetate, the organic layer was washed with brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 85 mg (91.39% Yield) of biphenyl-4-yl-methyl-amine.
Reaction SMILES: C(N(CC)C([S:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]([C:16]1[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=1[CH2:25][O:26][CH3:27])=O)=S)C.C(O)=O.Cl.CO>C(Cl)Cl>[CH3:27][O:26][CH2:25][C:17]1[N:18]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[S:20][C:16]=1[C:14]1[S:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:13]=1
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(NC(C)=O)nc1COC
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Solvent: CO
Product: COCc1nc(NC(C)=O)sc1-c1nc2ccncc2s1
Yield: 14.1 %

Procedure:
Crude 4-(2-acetamido-4-(methoxymethyl)thiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (4.485 g, 9.89 mmol) and formic acid (0.379 mL, 9.89 mmol) were added to a 150 mL round-bottomed flask, and the solution was stirred at reflux for approximately 24 hours until LCMS indicated that the reaction was complete. The formic acid was removed, and the reaction was quenched by addition of 1 N NaOH. No precipitate formed, and the solution was made neutral with HCl and extracted with EtOAc (5×75 mL) to provide crude product. The organic solution was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM, to provide N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.446 g, 1.39 mmol, 14.1% yield). LCMS (M+H) 321.1 calc. for C13H13N4O2S2 321.39, 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.61 (d, J=6.5 Hz, 1H), 8.18 (d, J=6.5 Hz, 1H), 4.82 (s, 2H), 3.51 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](=[O:43])[NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione hydrochloride (2.03 g, 4.65 mmol) and N-t-butoxycarbonylpyrrolidin-2-carboxylic acid (1 g, 4.65 mmol) in N,N-dimethylformamide (20 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (0.96 g, 4.65 mmol) was added to this solution and stirring was continued for 2 h at ambient temperature. Water (150 ml) was added to the reaction mixture, stirred for 20 minutes, ethyl acetate (200 ml) was added and stirring continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to give the crude compound, which was purified by column chromatography (1.42 g, yield 51.2%).