Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:22]([NH2:23])=[CH:21][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11][C:10]3([CH2:19][CH3:20])[C:4]=2[CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].COCCOC.CB1OB(C)OB(C)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:19]([C:10]12[CH2:11][CH2:12][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:18][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([NH2:23])[C:2]([CH3:24])=[CH:3][C:4]2=1)[CH3:20]
Reactant: CCC12CCC3(CC1CCOc1cc(N)c(Br)cc12)OCCO3
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCC12CCC3(CC1CCOc1cc(N)c(C)cc12)OCCO3
Temperature: 90 °C
Yield: 74.9 %

Procedure:
A 500 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (9.14 g, 23.9 mmol), bis(triphenylphosphine)palladium(II) chloride (0.839 g, 1.20 mmol) and Cs2CO3 (23.4 g, 71.7 mmol), and then DME (180 mL), water (60 mL) and trimethylboroxine (6.67 mL, 47.8 mmol) were added. The reaction mixture was heated to about 90° C. for about 15 h. The reaction was allowed to cool to rt and then it was partitioned between EtOAc (350 mL) and water (200 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were then washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (5.68 g, 74.8%) containing about 20% of a minor regioisomer. The material was used directly in Step #5 without further purification. LC/MS, method 3, 2.26 min, MS m/z 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:25]1[C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]([C:16]2[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:2]([F:1])[CH:17]=2)=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 73.1 %

Procedure:
Following General Procedure I, tert-butyl 2-fluoro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (1.1 g, 2.3 mmol) was reacted with NBS (540 mg, 3.1 mmol) to afford the desired product (920 mg, 70%) as a brown solid. ESI MS m/z 547 [C25H24BrFN2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl.[C:18](=N)(OCC)[CH2:19][CH2:20][CH3:21]>C(O)C>[C:7]1([C:5]([C:4]2[CH:13]=[CH:14][C:15]3[NH:16][C:18]([CH2:19][CH2:20][CH3:21])=[N:1][C:2]=3[CH:3]=2)=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cc(C(=O)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 3,4 diaminobenzophenone (21.2 g; 0.1 mol) and ethyl butyrimidate hydrochloride (22.7 g; 0.15 mol) in ethanol (500 mL) was heated at reflux for a period of 6 hours. The mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (EtOAc/Hexane; 1:1). Crystallization from ethyl acetate provided 12 g (45% yield) of the title compound as an off-white solid, m.p. 131-132° C. Anal. Calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.20; H, 6.06; N, 10.72. Mass spectrum (EI; M+) m/z 264. 1H-NMR (DMSO-d6; 400 MHz) δ12.56 (br s, 1H), 7.84 (s, 1H), 7.73 (m, 2H), 7.65 (m, 1H), 7.60 (s, 2H), 7.56 (t, 2H), 2.82 (t, 2H), 1.80 (m, 2H), and 0.95 ppm (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([OH:26])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]O>>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][O:25][C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:26]
Reactant: OCc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)OCc3ccccn3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid and 2-pyridinemethanol.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC1C=CC=CC=1S(O[CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O.CCOCC>CN(C)C=O.[Cl-].[Na+].O>[CH:3]1([CH2:8][O:9][CH2:21][C@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccccc1S(=O)(=O)OC[C@H]1COC(C)(C)O1
Reactant: OCC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC1(C)OC[C@H](COCC2CCCC2)O1
Reaction time: 18 h

Procedure:
Sodium hydride (0.63 g, 26.3 mmol) and cyclopentanemethanol (2.8 ml, 25.9 mmol) in dimethylformamide were heated at 50° for 30 min. The reaction mixture was cooled to 20° and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol 4-methylbenzenesulphonate (5.0 g, 17.5 mmol) added. The reaction mixture was heated at 50° for 30 min and left at 20° for 18 h. Ether and brine were added, the organic layer dried (Na2SO4) and the solvent evaporated to give the sub-title ether (3.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.CC(C)=O.[C:22]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][C:22]([CH3:24])([CH3:23])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:3]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thirty grams (0.11 mole) of 3-(4,6-dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane is dissolved in 300 ml. of acetone and then 370 ml. of water is added followed by 20 g. (0.15 mole) of tert-octylamine. After stirring for 10 minutes, 4.4 g. (0.11 mole) of NaOH in 30 ml. of water is added over 20 minutes. The reaction is then heated to reflux for 19 hours. After cooling to room temperature, one liter of water is added, stirred for one hour and the white precipitate filtered off. The precipitate is washed with water, dried overnight, dissolved in dichloromethane and filtered through Magnesol®. The Magnesol® is then washed with dichloromethane, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 20 g. of colorless crystals, m.p. 159°-162.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:31])[C:20]1[C:21](=[C:26](I)[CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH3:25])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][O:24][C:22](=[O:23])[C:21]1[C:20](=[C:29]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=1)[C:19]([O:18][CH3:17])=[O:31]
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN3CCOCC3)cc2)c1C(=O)OC
Yield: 70 %

Procedure:
A mixture of 4-(2-morpholin-4-yl-ethoxy)-phenylamine (1.4 g, 6.2 mmol), 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (60 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 1.8 g of the product at 95:5 methylene chloride-methanol, in 70% yield, as a pale yellow solid; 1H NMR (CDCl3) δ 3.00-3.51 (m, 6H), 3.87 (s, 3H), 3.88 (s, 3H), 4.08-4.34 (m, 4H), 4.52-4.62 (m, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.99 (d, J=7.1, 1H), 7.09-7.12 (m, 3H), 7.23-7.28 (m, 1H), 8.08 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[C:27]([N:29](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[N:29]
Reactant: COc1ncc(Br)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (100 mg), zinc cyanide (41.8 mg) and tetrakis(triphenylphosphine)palladium(0) (54.9 mg) in DMA was stirred under microwave irradiation at 120° C. for 30 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (61.7 mg).
Reaction SMILES: Cl.C[O:3][C:4]([CH3:24])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:22])[C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])=[N:12][CH:11]=1)[CH3:9].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31].S([O-])([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>ClC(Cl)C.CO.C(O)(=O)C>[OH:3][C:4]([CH3:24])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:22])[C@@H:17]([NH:21][CH:28]([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:26][CH3:25])[CH2:18][CH2:19][CH3:20])=[N:12][CH:11]=1)[CH3:9]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)CCCC(C)(C)OC)s1
Reactant: CCCCC(=O)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCC(CCC)N[C@@H](CCC)C(=O)Nc1ncc(C(C)CCCC(C)(C)O)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (100 mg, 0.265 mmol) and 3-heptanone (0.1 mL), acetic acid (0.2 mL), sodium sulfate and sodium cyanoborohydride (100 mg) in dichloroethane (2 mL) and methanol (1 mL) was stirred at 40° C. overnight. The mixture was quenched with water, basified by dilute sodium hydroxide, and extracted with methylene chloride. The organic layer was concentrated to dryness. The residue was purified by Biotage silica gel column chromatography to isolate 2-(S)-(1-propyl-butylamino)-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide as a colorless oil, LC-MS, RT=2.2 min, M+1=426.5.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:31])[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[Br:16])=[O:7].O.[OH-].[Li+].CO.C(O)(=O)C>C1COCC1.O>[Br:16][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:31])[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C(=O)N[C@@H](Cc2ccc(-c3cccn(C)c3=O)cc2)C(=O)O)c1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
A solution of N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (52 mg, 0.104 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (20 mg, 0.47 mmol) in water (1.0 mL). Methanol (0.5 mL) was added to effect a clear solution and the reaction mixture was stirred 18 hr. Acetic acid (0.5 mL) was added, the entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine (39 mg, 78%) as a white solid. HRMS: Obs. Mass 485.0703 Calcd. Mass 485.0712 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (1.67 g, 3.86 mmol), ethyl 2-(4-bromophenyl)acetate (1.127 g, 4.64 mmol) and potassium carbonate (1.602 g, 11.59 mmol) in toluene (10 mL) and ethanol (10.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.446 g, 0.386 mmol) under nitrogen. The reaction mixture heated at 100° C. for 1 h, then partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25 g), eluting with an EtOAc/cyclohexane gradient (10 to 80%). The appropriate fractions were combined and concentrated in vacuo to give ethyl 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetate (752 mg, 42%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=1.10 min, MH+=469.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:23]=[C:21]1[CH2:20][C:7]2[C:6](=[C:11]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cccc(Oc3ccccc3Cl)c2N1

Procedure:
A mixture of iron powder and ammonium chloride in ethanol and water and ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate were treated in a similar manner to that of Preparation 28-(1) to give 2-oxo-7-(2-chlorophenoxy)indoline
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C@H:27]([O:36][CH2:37]SC)[CH2:26]1.C1C(=O)N(I)C(=O)C1.[P:48](=[O:52])([OH:51])([OH:50])[OH:49].[O-]S([O-])(=S)=O.[Na+:58].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO>[P:48]([O-:52])([O-:51])([O:50][CH2:37][O:36][C@H:27]1[C@H:28]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH2:29][CH2:30][N:25]([C:3]2[CH:4]=[C:5]([C:23]#[N:24])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]4=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:26]1)=[O:49].[Na+:58].[Na+:58]
Reactant: O=P(O)(O)O
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OCSC)C3)c2Cl)nn2c(C#N)cnc12
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OCOP(=O)([O-])[O-])C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C

Procedure:
To a stirred solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((methylthio)methoxy)piperidin-4-yl)carbamate (18 mg, 0.032 mmol) in THF (2 mL) at 0° C. was added NIS (14.18 mg, 0.063 mmol) followed by crystalline phosphoric acid (15.44 mg, 0.158 mmol) and allowed to warm to room temperature in 1 h. After TLC showed completion of starting material, reaction mixture was diluted with methanol (2 ml) and treated with 1M Na2S2O3 until it becomes colorless, then pH adjusted to 10 (approx) by addition of solid Na2CO3. Resultant precipitate was removed by filtration and submitted for LC-MS, which showed major product. The filtrate was concentrated and lyophilized to give crude off white solid. This was purified by reverse phase preparative HPLC to give pure sodium (((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl)oxy)methyl phosphate (9 mg) as an off white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](O)=[O:30])[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:39])([CH3:38])[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](=[O:30])[NH:37][CH2:36][CH2:35][C:34]([CH3:39])([CH3:38])[CH3:33])[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH:19]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1C1=CCC(C)(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(C(=O)NCCC(C)(C)C)nn2c(C2=CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
To a mixture of (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylcyclohex-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (30 mg, 0.068 mmol) and 3,3-dimethylbutan-1-amine (13.69 mg, 0.135 mmol) in DMF (1.5 mL) was added DIEA (0.059 mL, 0.338 mmol), HATU (51.4 mg, 0.135 mmol) and DMAP (1.653 mg, 0.014 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ether (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.203 mL, 0.203 mmol) in MeOH (1.500 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(2-((3,3-dimethylbutyl)carbamoyl)-7-(4,4-dimethylcyclohex-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (23.6 mg, 0.045 mmol, 66.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.96 (t, J=5.8 Hz, 1H), 6.88 (s, 1H), 6.26 (br. s., 0.6H), 5.85 (br. s., 0.4H), 5.38 (s, 0.6H), 5.28 (s, 0.4H), 3.37-3.28 (m, 4H), 2.66 (s, 1H), 2.59 (s, 2H), 2.19-1.97 (m, 2H), 1.68-1.50 (m, 2H), 1.47 (t, J=7.9 Hz, 2H), 1.19 (s, 3H), 1.15 (s, 6H), 1.12 (s, 3H), 1.07 (s, 3H), 0.94 (s, 9H). LCMS (M+H)=499.4.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C@@H:17]3[C@@H:12]([NH:13][CH2:14][CH2:15][CH2:16]3)[CH2:11]2)(=O)=O)=CC=1.Br.C(O)(=O)CC.C1(O)C=CC=CC=1>>[C@H:12]12[CH2:11][NH:10][CH2:18][C@H:17]1[CH2:16][CH2:15][CH2:14][NH:13]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H]3CCCN[C@H]3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: C1CN[C@H]2CNC[C@H]2C1
Yield: 84.4 %

Procedure:
The title compound (9.12 g) is prepared from mixture system of (R,R)-6-(toluene-4-sulfonyl)-octahydro-pyrrolo[3,4-b]pyridine (24.0 g), hydrobromic acid (48%, 156 ml), propionic acid (72 ml) and phenol (14.6 g) following the same procedure described in example 9. After conventional work up and distillation 3.4 g of oil is obtained (yield: 78.0%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=2)=[O:27])[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(Cl)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH2:13])[C@H:7]3[C:6]=2[C:5]([F:14])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]=[C:27]=[S:28])=[N:24][CH:25]=1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]5[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=5)=[CH:25][N:24]=4)=[S:28])[C@H:7]3[C:6]=2[C:5]([F:14])=[CH:4][CH:3]=1
Reactant: N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@H]12
Reactant: Fc1cccc(Oc2ccc(N=C=S)nc2)c1
Solvent: CC#N
Product: Fc1cccc(Oc2ccc(NC(=S)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-amine (20 mg, 0.1 mmol) was dissolved in dry acetonitrile (1 ml) and 5-(3-fluorophenoxy)-2-isothiocyanatopyridine (25 mg, 0.1 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 h. The precipitate formed was collected by filtration and washed with acetonitrile and diethyl ether to give 17 mg (38% yield) of pure product as beige powder.