Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[OH2:32]>CN(C=O)C>[ClH:1].[NH2:9][CH2:7][CH2:5][CH2:4][CH2:3][C:2]([N:9]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[CH2:12]1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:32]
Reactant: O
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: NCCCCC(=O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.83 g (6.5 mmol) of compound (A) are dissolved in 100 ml of abs. DMF under argon. 468 mg (19.5 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 7.6 g (19.5 mmol) of Example 10A, dissolved in 10 ml of DMF, are added. Stirring is continued at RT for a further 15 min and the batch is then admixed with 20 ml of water added gradually. Thereafter the batch is concentrated and the residue is stirred up with 150 ml of saturated solution of hydrogen chloride in dichloromethane for 1 h, during which the bis-acyl compound initially formed after enolization, with mass M=1141, is cleaved. This is followed by concentrating and the residue is taken up in 700 ml of ethyl acetate and extracted twice with 200 ml each time of 10% sodium carbonate solution. The organic phase is separated off, concentrated and taken up in 30 ml of ethyl acetate and then admixed with 30 ml of diethyl ether. After brief stirring, undissolved residues are filtered off and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 4:1 as eluent. The appropriate fractions are concentrated and the residue is taken up in 10 ml of ethyl acetate. 100 ml of cold diethyl ether are added and the batch is left to stand at 0° C. for 30 min. After filtration, the residue is treated once more with 100 ml of diethyl ether. After renewed filtration, the filter residue is collected and dried to obtain 1 g (20% of theory) of the compound fully protected at the amino group.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[C:15]3[Cl:20])C=CC=CC=1.Cl.[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH2:41])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH:41][C:8]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[Cl:20])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Nc1cccc2c(Cl)nccc12)Oc1ccccc1
Reactant: NC1CCc2cc(F)ccc2C1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1cccc2c(Cl)nccc12)NC1CCc2cc(F)ccc2C1Cc1ccccc1
Yield: 27.8 %

Procedure:
(1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150 mgs, 0.5 mmol), 1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (146 mgs, 0.5 mmol), and sodium bicarbonate (42 mgs, 0.5 mmol) were combined and stirred for one hour in DMSO (4 ml) at ambient temperature. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoquinolin-5-yl)-urea (64 mgs, 28%) MS (MH+) 459; 1H NMR (CD3OD) δ 1.93-2.06 (m, 1H), 2.09-2.13 (m, 1H), 2.91-3.07 (m, 4H), 3.40-3.42 (m, 1H), 4.07-4.10 (s, 1H), 6.69-6.78 (m, 1H), 6.80-6.89 (m, 2H), 7.12-7.26 (m, 5H), 7.72 (t, 1H, J=8.2 Hz), 7.83 (d, 1H, J=6.1 Hz), 8.19 (d, 1H, J=8.6 Hz), 8.17-8.24 (m, 2H). HPLC Rt=4.04 min (50-90% water:acetonitrile gradient, 100% pure).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([O-])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:12].[CH:13]([O-])([O-])OC>CO>[I:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:13][NH:12][C:7]2=[O:8]
Reactant: COC([O-])[O-]
Reactant: Nc1ccc(I)cc1C(=O)[O-]
Reactant: [NH4+]
Solvent: CO
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 530 mg (1.9 mmol) of ammonium 5-iodoanthranilate (prepared in the same manner as in Reference Example 4), 403 mg (3.8 mmol) of methyl orthoformate, and 1.5 mL of methanol. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 402 mg (reaction yield: 77%) of 6-iodoquinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]#[N:22].S(=O)(=O)(O)[OH:24]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([NH2:22])=[O:24]
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Temperature: 0 °C
Yield: 99 %

Procedure:
5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile and 10 ml of 96 % sulfuric acid are stirred for 4 hours at room temperature. The batch is added to 50 g of ice, the precipitate is separated by vacuum filtering and washed with water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide is obtained with a 99% yield; F 192°-193°.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22]Br)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]>CN(C)C=O.O>[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]
Reactant: Sc1ccccc1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CBr)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a solution of thiophenol [425 mg (3.8 mmol)] in dimethylformamide (10 ml) was added, under ice-cooling, sodium hydride [167 mg (4.2 mmol, content:60%)]. To the reaction mixture was added, after stirring for 20 minutes, a solution of 5-acetoxy-2-bromomethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.8 mmol)] dimethylformamide (5 ml). The mixture was stirred for further 30 minutes. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and concentrated. The concentrate was crystallized from isopropylether-hexane to afford 5-acetoxy-4,6,7-trimethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran (Compound 4) [1.2 g (yield : 91.3%)]. In a manner as above, compounds 2, 6, 8, 10, 12 and 18 were synthesized by employing the corresponding thio compounds (3-mercaptopropionic acid, 1-octanethiol, 2-mercaptopyridine, 4-fluorothiophenol, 2-naphthalene thiol and benzyl mercaptan). Incidentally, when 3-mercaptopropionic acid was employed as the starting compound, 2.2 equivalents of sodium hydride was used.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][NH2:12])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([CH2:11][NH:12][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]([CH:26]4[CH2:28][CH2:27]4)[NH:24][N:25]=3)[CH:17]=[CH:16][N:15]=2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cc2nc[nH]c2cc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2[nH]cnc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A tube was charged with 252 (110 mg, 0.608 mmol), 53 (143 mg, 0.608 mmol), and DIPEA (235 mg, 1.823 mmol) in IPA (3 mL), sealed and heated 120° C. for 18 h with stirring. The reaction was cooled to RT and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 72 mg (31.3%) of I-94 as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[N:24]1[C:20](=[O:30])[C:21]2[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of [3-(3-chloro-phenyl)-3-hydroxy-propyl]carbamic acid tert-butyl ester (12 g, 42 mmol), phthalimide (6.2 g, 42 mmol), and PPh3 (14.3 g, 55 mmol) in THF (150 mL) was added DEAD (9.0 mL, 55 mmol) dropwise at about 5° C. After 1 hour, the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:8) to afford [3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester. (Yield 15.65 g, 90%). LC-MS: [M+H]+ 415.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:35][N:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCOCC2)cn1
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.442 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.142 g, 17.6%). MS (APCI); M++1: Calc'd, 451.3, Found 451.3. Anal. Calc'd for C25H32N6O2: C, 63.98; H, 6.71; N, 18.65. Found; C, 64.03; H, 6.66; N, 18.49.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH3:6].[Mg].[CH3:8][S:9][CH2:10][CH2:11][CH:12]=[O:13].[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:8][S:9][CH2:10][CH2:11][CH:12]([OH:13])[CH2:2][CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCCCl
Reactant: CSCCC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSCCCC(O)CCSC
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloro-3-methylthiopropane (3.73 g, 30 mmole) in dry THF (50 mL) was added to stirred magnesium turnings (0.72 g, 30 mmole) under argon. Once the addition was complete, the mixture was heated to 50° C. for 3 hours. The mixture was then allowed to cool to room temperature and 3-methylthiopropanal (3.12 g, 30 mmole) was added. The reaction was stirred at room temperature for 1 hour. 2M ammonium chloride solution (50 mL) was added, followed by ether (50 mL). The organics were separated, dried, filtered, and evaporated to give a pale yellow oil that was purified by chromatography in 40-60 petroleum ether/ether (4/5) to give 5 (2.1 g, 36%) as a colorless oil.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:36][CH2:35][C:34]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)([OH:33])[CH2:39][CH2:38]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3cncs3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (30.0 mg, 0.0846 mmol) from Step C-2 of Example 1 and 4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexanone (23.4 mg, 0.119 mmol) in dichloromethane (8 mL) was added triethylamine (0.0236 mL, 0.169 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol) at room temperature. After being stirred overnight, the mixture was diluted with dichloromethane and neutralized with saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give two isomers. LC-MS for both isomers: calculated for C28H36F3N3O2S (M+H)+536; found 536.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[F:22])(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:37][C:38]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[O:41]>N1C=CC=CC=1.CN(C=O)C>[C:40]([C:39]1[C:38]2[N:37]=[C:1]([C:4]3[CH:9]=[CH:8][C:7]([CH:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=3[F:22])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)(=[O:41])[NH2:42]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)c(F)c1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 50D (1.48 g) in pyridine (5 mL) and DMF (5 mL) was added CDI (0.856 g). The solution was stirred at 45° C. for 2 hours, treated with 2,3-diaminobenzamide dihydrochloride (1.08 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (30 mL), and this solution was heated at 80° C. for 3 hours and concentrated. The concentrate was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 0-15% methanol in 2:1 ethyl acetate/hexane.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C>C(#N)C>[Br-:6].[O:13]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCSC1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)C[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.4 %

Procedure:
In 100 ml of acetonitrile was dissolved 11.8 g of tetrahydrothiophene, to the solution was gradually added 20 g of 1-bromo-3,3-dimethyl-2-butanone. The mixture was stirred at room temperature for 2 days to deposit powder. After adding 100 ml of ethyl acetate to the reaction solution, the powder was collected by filtration, washed with ethyl acetate and dried to obtain 24 g of 2-oxo-3,3-dimethylbutyltetrahydrothiophenium bromide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1([O-:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[O:21]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [O-]c1ccccc1
Reactant: O=Cc1cc(-c2ccccc2)c(Br)s1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2)c(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 5-bromo-4-phenylthiophene-2-carbaldehyde (652 mg) in N,N-dimethylformamide (10 mL) was added sodium phenolate (425 mg) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→9:1) to give the title compound as a pale-yellow solid (yield 152 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[NH4+:23].[OH-]>C(O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:23])=[O:13])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: [NH4+]
Reactant: O=C(O)c1cc(Br)c2c(c1)CCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)c1cc(Br)c2c(c1)CCC2
Yield: 68 %

Procedure:
7-Bromoindane-5-carboxylic acid (2.9 g, 12 mmol) and oxalylchloride (2.0 g, 16 mmol) were mixed with CH2Cl2 (50 mL) whereupon DMF (100 mg) was added. After 1 h at room temperature the mixture was poured into a mixture of concentrated NH4OH aq (20 mL) and ethanol (100 mL). The volatiles were removed by evaporation and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the solid residue was treated with cold CH2Cl2, then filtered off and dried. There was obtained 2.0 g (68%) of 7-bromoindane-5-carboxamide as a solid material. 1H NMR (300 MHz, CD3CO CD3): 2.0-2.2 (m, 2H), 2.8-2.9 (d, 2H), 2.9-3.0 (t, 1H), 3.0-3.1 (t, 1H), 6.5 (b, 1H), 7.4 (b, 1H), 7.7 (s, 1H), 7.9 (s,1H).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: Clc1nccnc1OC1CCCN(c2ccc3ccccc3n2)C1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: OCC1CCN(c2nccnc2OC2CCCN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (racemix mixture) (see PREPARATION P2.3; 0.1 g, 0.29 mmol) and piperidin-4-ylmethanol (0.033 g, 0.29 mmol) and K2CO3 (0.08, 0.58 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.020 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 420 calc. for C24H29N5O2 419.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:37])([CH3:36])[CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:28][CH2:27][CH2:26][CH2:25][C:24]([NH:23][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:22])([CH3:36])[CH3:37]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCN)c3n2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 58 %

Procedure:
To a stirred solution of tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 0.15 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and the solution stirred for 2 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(5-amino-2-methylpentan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (35 mg, 58%) as a pale yellow solid. MS: (M+H)+=410; 1H NMR (300 MHz, DMSO): δ 12.98 (s, 1H), 9.11 (s, 1H), 8.49-8.42 (m, 2H), 7.88 (s, 1H), 7.74 (d, 1H, J=9.9 Hz), 7.60 (brs, 3H), 7.20 (t, 1H, J=9.0 Hz), 4.18 (s, 3H), 2.76 (brs, 2H), 2.00-1.94 (m, 2H), 1.61 (brs, 2H), 1.25 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Na+].BrC[CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1.O.[CH3:24]N(C)C=O>>[O:19]1[CH2:18][CH2:17][CH:22]([CH2:24][N:7]2[C:6]3[CH:12]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: BrCC1CCCOC1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2c(c1)N(CC1CCOCC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
4.9 g (0.03 mole) of 6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one in 50 ml of dimethylformamide are initially taken, 0.79 g (0.033 mole) of sodium hydride is added at 5° C. and the mixture is stirred for 30 minutes at this temperature. Thereafter, 5.9 g (0.033 mole) of 3-bromomethyltetrahydropyran are added, stirring is continued for 3 hours at 60° C., 200 ml of water are added the mixture is extracted twice with 200 ml of methylene chloride, the extracts are dried and the solvent is evaporated under reduced pressure. 5 g (64%) of 4-(tetrahydropyran-4-ylmethyl)-6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one (oil) are obtained.