Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][CH:7]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:2].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C=O)C.C(#N)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][CH:7]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:32][CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1c[nH]cn1)NC(=O)CCCCCCc1ccccc1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)C=CC(Cc1cn(CC=Cc2ccccc2)cn1)NC(=O)CCCCCCc1ccccc1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
The 5-(1H-Imidazol-4-yl)-4-(7-phenyl-heptanoylamino)-pent-2-enoic acid ethyl ester (100 mg, 0.25 mmol) in DMF (1 mL) was treated with NaH (10 mg, 60%, 0.25 mmol) at room-temperature. After 5 minutes cinnamyl bromide (50 mg, 0.25 mmol) was added, and the solution stirred overnight. Analytical HPLC showed the product was a 60:40 mixture of τ (required) and π (undesired) isomers respectively. The solution as taken up into water and acetonitrile and subject to reverse phase HPLC (30% B to 100% B over 25 min). The product, a mixture of both isomers, was obtained as an oil (88 mg, 68%), ESMS 514 (M+H+). 13C NMR δ 174.72, 174.67, 174.22, 171.69, 170.52, 166.20, 145.85, 142.93, 138.31, 138.16, 137.81, 137.45, 134.89, 134.81, 133.37, 132.86, 131.49, 131.39, 129.26, 128.98, 128.52, 128.34, 127.04, 125.68, 122.23, 119.68, 119.61, 119.54, 118.93, 114.55, 63.08, 61.90, 60.91, 60.79, 57.59, 54.77, 52.59, 52.53, 51.49, 50.21, 37.04, 36.14, 35.99, 33.44, 31.44, 29.61, 29.18, 29.13, 29.03, 28.97, 25.67, 25.62, 25.46, 14.27, 14.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[C:13]([CH:18]=C)[CH:12]=[CH:11][C:10]=3[C:9]2=[O:20])=[CH:5][CH:4]=1.C[OH:24].[BH4-].[Na+]>C(Cl)Cl>[OH:24][CH2:18][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:20])[N:8]([CH2:7][C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: C=Cc1ccc2c(n1)CCN(Cc1ccc(OC)cc1)C2=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCc3nc(CO)ccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-(4-Methoxybenzyl)-2-vinyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1 g, 4.49 mmol) from above was dissolved in a 1:1 mixture of DCM:MeOH, (50 mL) and cooled to −78° C. Ozone was bubbled through for 30 min. The reaction was warmed to 0° C. then NaBH4 (400 mg, 10.8 mmol) was added and the cold bath removed. After 10 min, the reaction mixture was quenched with Rochelle's Salt (20% solution, 50 mL) and diluted with EtOAc (100 mL). The organics were dried and concentrated to give 980 mg (96%). LC-MS (M+H)=299.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][NH2:23])([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.[OH-].[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH2:22][NH:23][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([Cl:31])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(CN)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CNC(=O)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
To a solution of 4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (12.2 mg, 0.037 mmol) and triethylamine (16 μL, 0.12 mmol) in dry dichloromethane (4 mL) was added 4-chlorobenzoyl chloride (5 μL, 0.037 mmol). After stirring for 18 hours at room temperature, the reaction mixture was partionated between dichloromethane (2 mL) and water (1 mL) with 10% aqueous sodium hydroxide (0.1 mL). The two layers were separated and the aqueous phase was further extracted with dichloromethane (2 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Preparative TLC, eluting with 10% methanol-dichloromethane, gave 4-tert-butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 0.013 mmol, 35%). LC-MS (LCT2) m/z 490 [M+Na+], Rt 8.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)nc(OC)c1
Temperature: 25 °C

Procedure:
Mix commercially available 2-chloro-6-methoxy-isonicotinic acid (17 g, 90.6 mmol), concentrated sulfuric acid (0.85 mL) in methanol (150 mL) and reflux overnight. Cool the mixture to room temperature, filter and dry the solid under vacuum to give the title compound (15.5 g). Concentrate filtrate and dilute with ethyl acetate (150 mL). Wash with sodium bicarbonate solution, water, dry (sodium sulfate) and concentrate to give additional title compound (1.7 g) (17.2 g, 93% combined yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[C:13]1([CH:12]=[N:11][N:7]2[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:9][C:8]2=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C1OC(CCCCl)CN1N=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1OC(CCCN2CCCCC2)CN1N=Cc1ccccc1
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A stirred solution of 5-(3-chloropropyl)-3-phenylmethyleneamino-2-oxazolidinone (2.7 g, 0.0101 mole), dimethylformamide (75 ml) and piperidine (2.15 g, 0.0253 mole, 2.5 eq.) is heated to reflux. Reflux is maintained for 2 hours. After cooling, the solution is concentrated under reduced pressure to a solid-oily residue. This residue is suspended in H2O (200 ml) then extracted with ethyl acetate (3×100 ml). The ethyl acetate is dried over MgSO4, filtered, then concentrated under reduced pressure to an oily-solid residue. This residue is triturated in hexane by stirring 1 hours. The solid is collected and air-dried giving 1.67 g (0.0053 mole) of 3-phenylmethyleneamino-5-[3-(1-piperidinyl)propyl]-2-oxazolidinone.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:16]=1[C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[F:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1ccccc1F
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccccc2F)nc2nc[nH]n12

Procedure:
Compound 43 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-fluorobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:20]([O:22][CH:23]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:27]([O:26][C:24](=[O:25])[C:23]([O:22][CH2:20][CH3:21])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[CH3:28]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Temperature: -10 °C
Yield: 50.7 %

Procedure:
4-Benzyloxy-3-methoxybenzaldehyde (7 g; 28.8 mmole) and (1,2-diethoxy-2-oxoethyl) (triphenyl)phosphonium chloride (13.6 g; 31 mmole) was dissolved in isopropanol and the reaction mixture was cooled to −10° C. Potassium carbonate (6 g; 43 mmole) was added. The resulting mixture was stirred over night and the temperature was allowed to reach room temperature. The reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added to the residue and the resulting mixture was stirred for a while and then insoluble material was filtered off. The filtrate was washed with potassium hydrogensulfate solution and water, dried with magnesium sulfate and evaporated. Isopropylether was added to the residue. Triphenylphosphine oxide precipitated and was filtered off and the filtrate was evaporated. Chromatography of the residue on silica gel using toluene with ethyl acetate (0, 1%, 3%) as eluant gave 5.2 g of 3-(4-benzyloxy-3-methoxyphenyl)-2-ethoxyacrylic acid ethyl ester. Since the product was not pure enough it was stirred with petroleum ether, insoluble material was filtered off and the filtrate was evaporated to give 4 g (38% yield) of pure 3-(4-benzyloxy-3-methoxyphenyl)-2-ethoxyacrylic acid ethyl ester.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([F:32])=[C:17]2[C:22]=1[NH:21][CH:20]=[C:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:18]2=[O:31])C1C=CC=CC=1>[C].[Pd].C(O)C>[F:32][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[C:22]2[C:17]=1[C:18](=[O:31])[C:19]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:20][NH:21]2
Reactant: COc1ccc(-c2c[nH]c3c(OCCCOCc4ccccc4)ccc(F)c3c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3c(OCCCO)ccc(F)c3c2=O)cc1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 53 %

Procedure:
8-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (1.95 g, 4.49 mmol) and a 10% palladium carbon (720 mg) were added to ethanol (50 ml). The mixture was stirred at 50° C. for 7.5 hours under a hydrogen atmosphere (1 atmosphere) and subjected to a catalytic reduction. The reaction mixture was cooled to room temperature, and filtration with Celite was conducted to remove the solvent. The filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=80:1→20:1). The purified product was concentrated under reduced pressure, and the residue was concentrated to dryness to thereby obtain 820 mg of pale dark brown amorphous solid 5-fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][C:31]([F:34])([F:33])[C:30](=[O:35])[NH:29][C:28]=2[CH:36]=1.Cl.O1CCOCC1>>[F:34][C:31]1([F:33])[C:30](=[O:35])[NH:29][C:28]2[CH:36]=[C:24]([NH:23][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)[CH:25]=[CH:26][C:27]=2[O:32]1
Reactant: Nc1ccc2c(c1)NC(=O)C(F)(F)O2
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2cc3nccc(Nc4ccc5c(c4)NC(=O)C(F)(F)O5)c3o2)cc(OC)c1OC
Temperature: 150 °C
Yield: 25.9 %

Procedure:
To a 10 mL microwave vial with stirbar was added 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (25.00 mg; 0.08 mmol; 1.00 eq.) and 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one (16.43 mg; 0.08 mmol; 1.05 eq.). The vial was sealed and flushed with N2 and the reagents were dissolved in NMP (1.00 ml). Hydrogen chloride in dioxane (0.02 ml; 4.00 M; 0.08 mmol; 1.05 eq.) was added and the reaction mixture was heated to 150° C. in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and quenched with NaOH(aq), extracted with EtOAc, dried (MgSO4) and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (2-10% MeOH/CH2Cl2 15 column vol.; 10% MeOH/CH2Cl2 5 column vol.) to afford the title compound as a beige solid (10 mg, 26%). (HPLC (method F): 90%, RT: 4.69 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.99 (s, 1H), 9.14 (s, 1H), 8.17 (d, J=5.5, 1H), 7.57 (s, 1H), 7.35 (d, J=8.8, 1H), 7.22 (s, 2H), 7.08-7.00 (m, 2H), 6.88 (d, J=5.5, 1H), 3.85 (s, 6H), 3.72 (s, 3H); MS (m/z) 484 [M+H]+, RT: 2.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C[N+]1([O-])CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CS(C)=O>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][C:20]([N:17]2[CH2:16][CH2:15][C:13]3[NH:14][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][C:7]=4[C:12]=3[CH2:18]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[N+]1([O-])CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
A mixture of 1.5 g (5.8 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.979 g (5.8 mmol) of ethyl 4-fluorobenzoate, 0.68 g (5.8 mmol) of 4-methylmorpholine N-oxide, 3.78 g (11.6 mmol) of Cs2CO3 and 10 ml of dimethylsulfoxide is stirred overnight at 80° C. The reaction mixture is allowed to cool and is diluted with water to yield a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.055 g (2%) of the title compound as a yellow solid: m.p. 241°-243° C.; m/e 405.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:26](OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:26])[C:9]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CCc2ccccc2C1
Reaction time: 48 h

Procedure:
To 2-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (291 mg, 1.0 mmol) in DMF (2.0 mL) was added MeI (710 mg, 5.0 mmol) and NaH (50%, 250 mg, 5.0 mmol) at 0° C. Ethyl acetate (50 mL) was added after 3 days and the mixture was washed with water (3×15 mL). The material (380 mg) was taken up in methanol (5.0 mL) and water (3.0 mL) and NaOH (10 M, 3.0 mL) was added. After 2 days, 10% HCl was added to adjust the pH˜2 and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were concentrated in vacuo to provide the titled acid.
Reaction SMILES: C(O[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)[C:31]1[C:32]([O:37][CH3:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:7]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(C)CN(CC(=O)N1CCC[C@H]1C#N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)N(CC(=O)N1CCC[C@H]1C#N)CC(C)C
Temperature: 0 °C
Yield: 64.2 %

Procedure:
(2S)-1-(2-(N-tert-Butyloxycarbonyl-N-(2-methylpropyl)amino)acetyl)pyrrolidine-2-carbonitrile (25 mg, 0.081 mmol) was treated with trifluoroacetic acid (50 ml). After 1 h at room temperature the solvent was removed in vacuo and the residue dissolved in CH2Cl2 (100 ml). The solution was cooled to 0° C., triethylamine (30 mg, 0.3 mmol) was added followed by 2-anisoyl chloride (15 mg, 0.088 mmol). After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue dissolved in ethyl acetate (200 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 2% methanol, 98% chloroform) to give a colourless oil identified as the title compound (18 mg, 0.052 mmol, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[CH3:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1Nc1ccccc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(c1ccccc1)C(=O)[C@H]1CC[C@H](C)CC1

Procedure:
The methyl ester from Step I (565 mg, 1.13 mmol) was acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described (example 11, step II) to give 41 mg (27%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-phenyl-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.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]>[Cl:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: CN1CCn2nc(N)cc2C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Temperature: 90 °C
Yield: 55.9 %

Procedure:
A solution of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (55.7 mg, 0.37 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (81.8 mg, 0.37 mmol) cesium carbonate (417 mg, 1.28 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31.8 mg, 0.05 mmol) in dioxane (6 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (25.1 mg, 0.03 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 2% to 7% methanol in dichloromethane) to give 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (61 mg, 57%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:6]([CH:15]=[CH2:16])[N:7]=1
Reactant: Nc1nc(Cl)nc(N2CCCCC2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc(N)nc(N2CCCCC2)n1
Temperature: 100 °C

Procedure:
To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was added tributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh3)4 (97 mg, 0.084 mmol) and the reaction mixture was heated at 100° C. for 16 h in a sealed tube. Then, the reaction mixture was allowed to cool to room temperature, concentrated, and purified directly by flash chromatography on silica gel (AcOEt/hexane: 10/90→430/70) to afford the title compound 222 (containing tributyltin chloride).
Reaction SMILES: C[C:2]1[CH:9]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=3[CH3:26])[C:14]([N+:27]([O-:29])=[O:28])=[C:13]([CH3:30])[N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[CH:36](N(C)C)[N:37]([CH3:39])[CH3:38])(C)(C)C>CN(C=O)C>[Br:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([NH:17][C:15]2[C:14]([N+:27]([O-:29])=[O:28])=[C:13](/[CH:30]=[CH:36]/[N:37]([CH3:39])[CH3:38])[N:12]=[C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[CH:2][CH:9]=3)[N:16]=2)=[C:19]([CH3:26])[CH:20]=1
Reactant: Cc1cc(Nc2nc(C)c([N+](=O)[O-])c(Nc3c(C)cc(Br)cc3C)n2)ccc1C#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Nc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A dried flask under argon was charged with methyl 4-(4-(4-bromo-2,6-dimethylphenylamino)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (4.3 g, 9.5 mmol) dissolved in anhydrous DMF (95 ml) followed by tert-butoxybis(dimethylamino)methane (2.4 ml, 11.4 mmol). The reaction mixture was heated to 60° C. and stirred overnight under argon. Upon completion the reaction was cooled to ambient temperature, concentrated to half volume, and quenched with H2O (100 ml). The aqueous solution was extracted with ethyl acetate (3×70 ml) and the collected organic fractions were washed with brine (100 ml), dried with MgSO4, filtered and concentrated. Silica gel chromatography (ethyl acetate: Hexanes=50:50) yielded (E)-4-(4-(4-bromo-2,6-dimethylphenylamino)-6-(2-(dimethylamino)vinyl)-5-nitropyrimidin-2-ylamino)benzonitrile (3.21 g, 67%) as a brown solid. m/z=508 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:31])[CH2:29]O)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(Cl)Cl.C1(C)C=CC=CC=1.C1C=CC(OP(OC2C=CC=CC=2)([N:51]=[N+:52]=[N-:53])=O)=CC=1.N12CCCN=C1CCCCC2>>[N:51]([CH2:29][C@H:28]([N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:26])[C:16]=2[NH:15][C:13](=[O:14])[CH2:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([F:1])[CH:3]=2)[C:21]1=[O:27])[CH3:31])=[N+:52]=[N-:53]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(=O)n([C@H](C)CN=[N+]=[N-])ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
A solution of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (0.5 g, 0.001 mol) in methylene chloride (20 mL, 0.3 mol) and toluene (10 mL, 0.09 mol) was cooled to 0° C. and treated with diphenylphosphonic azide (600 mg, 0.002 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 g, 0.002 mol) under nitrogen. The mixture was stirred at 0° C. for 2 h then allowed to warm to room temperature and was stirred overnight. The mixture was concentrated and the residue was treated with water (50 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine, dried and evaporated. The residue was purified via flash chromatography to afford the desired product as a clear oil (0.48 g, yield 90%).