Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.39 mmol) was dissolved in 10 mL of DMF. Glycine (0.58 g, 7.75 mmol) and sodium ethoxide (0.40 g, 5.81 mmol) were added and the mixture was refluxed for 14 h. The mixture was cooled to room temperature and diluted with 60 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 70 mg of the title compound. MS: (+) m/z 314.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:12].[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH:45][C:3]([C:4]1[CH:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:12])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Yield: 1016.1 %

Procedure:
4-Amino-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (3.0 g) was prepared from 2-amino-5-bromobenzoic acid methyl ester (4.58 g, 20 mmol) and 4-trifluoromethylphenyl boronic acid (4.75 g, 25 mmol) following general procedure D, then hydrolyzed following general procedure C. The above acid (281 mg, 1.0 mmol) was reacted with 2(S)-amino-3-(3′chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (343 mg, 1.0 mmol) as described in general procedure A to give the title compound. (300 mg)
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.[CH:37]1[CH:41]=[C:40]([CH2:42][NH2:43])[O:39][CH:38]=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:43][CH2:42][C:40]3[O:39][CH:38]=[CH:37][CH:41]=3)=[O:24])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: NCc1ccco1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 57.4 %

Procedure:
4-[(9aS)-2-(2,4-Difluorobenzyl)-3-(ethoxycarbonyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.120 g, 0.244 mmol) was dissolved in 2 mL DCM. 2-Furfurylamine (0.035 g, 0.365 mmol) was added followed by EDC (0.070 g, 0.365 mmol). After 3 h, the reaction mixture was diluted with EtOAc and washed with pH 4.0 buffer (3×), saturated NaHCO3, brine, and dried over MgSO4. Purification on SiO2 (hexanes:EtOAc 1:1 to 1:2) provided the title compound as a white solid (0.082 g, 0.14 mmol, 59%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.17 (m, 1H), 6.78 (m, 2H), 6.43 (t, J=5.2 Hz, 1H), 6.34 (m, 1H), 6.30 (m, 1H), 4.69 (dd, J=12.4, 6.4 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 4.31 (AB, J=15.6, 2H), 3.90 (dq, J=7.2, 2.0 Hz, 2H), 3.68 (m, 1H), 3.35 (m, 1H), 2.45 (m, 1H), 2.30 (m, 2H), 1.38 (m, 1H), 0.85 (t, J=7.2 Hz, 3H) ppm. ESMS m/z 572 (M+H)+, 604 (M+Na)+. Anal. calcd. for C32H27F2N3O5.¼H2O: C, 66.72; H, 4.81; N, 7.29; found: C, 66.70; H, 4.70; N, 7.21.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH2:21][NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][N:22]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)[C:8]([C:7]1[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1])=[O:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COC(=O)C(C)(C)COc1ccc(NCCO[Si](C)(C)C(C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2c(Cl)ncnc2Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (130.5 mg, 0.617 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added dropwise to a solution of methyl 3-(5-(2-(tert-butyldimethylsilyloxy)ethylamino)pyridin-2-yloxy)-2,2-dimethylpropanoate B-18 (157.2 mg, 0.411 mmol) and triethylamine (124.5 mg, 1.233 mmol) in anhydrous tetrahydrofuran (5.0 mL) at 0° C. The reaction mixture was stirred for 30 mins, then allowed to warm to room temperature, stirred for an additional 2 h period and then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 3-(5-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)pyridin-2-yloxy)-2,2-dimethylpropanoate B-19 (150 mg, Yield=66%). MS (ESI) [M+1]+ 558.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:5][CH:4]=1
Reactant: CNc1nccc(-c2cc(NCCCN3C(=O)c4ccccc4C3=O)c3cc(OC)ccc3c2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1nccc(-c2cc(NCCCN)c3cc(OC)ccc3c2)n1
Temperature: 80 °C

Procedure:
To a solution of 2-(3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl) amino)propyl)isoindoline-1,3-dione 181 (95 mg) in ethanol (10 ml) was added hydrazine hydrate (0.1 ml) and the mixture stirred at 80° C. 3 hours. After cooling the mixture in an ice bath the precipitate formed was filtered off and washed with ice cold ethanol. The filtrate was evaporated to dryness to yield N1-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl) propane-1,3-diamine 182 as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:33][CH2:32][CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cn(C)c3ccc(C(=O)O)cc3c2=O)cc1
Reactant: NCCN1CCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cn(C)c3ccc(C(=O)NCCN4CCCC4)cc3c2=O)cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a suspension of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (Example 5e) (0.588 g, 1.733 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.240 ml, 1.906 mmol), EDC (0.3865 g, 2.016 mmol), HOAt (0.1218 g, 0.895 mmol) in dichloromethane (16 ml) was added triethylamine (1.7 ml, 12.20 mmol), and the mixture was allowed to stir at 30° C. for 24 h. After cooling, the reaction was concentrated and the residue was purified on a silica gel column (24 g), eluting with 0-20% methanol/dichloroethane (2% ammonium hydroxide). The desired fractions were collected, concentrated. The solid was washed with water, filtered, and dried in vacuo to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-6-carboxamide (0.595 g, 1.366 mmol, 79% yield) as white solid. LCMS: (M+H)+: 436.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]1O[CH2:9][C@@H:8]([CH3:11])[N:7]([C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22](F)[CH:21]=3)[CH:13]=2)[CH2:6]1)[CH3:3].[OH2:29].[NH2:30][NH2:31]>O1CCOCC1>[CH3:1][N:2]([CH2:4][C@H:5]1[O:29][CH2:11][C@@H:8]([CH3:9])[N:7]([C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([C:20]3[CH:27]=[C:26]4[C:23]([C:24]([NH2:25])=[N:30][NH:31]4)=[CH:22][CH:21]=3)[CH:13]=2)[CH2:6]1)[CH3:3]
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Reactant: O
Reactant: NN
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
A mixture of 4-[6-{(2R,5R)-2-[(dimethylamino)methyl]-5-methyl-4-morpholinyl}-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (58 mg, 0.15 mmol) and hydrazine monohydrate (0.10 mL, 3.21 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. in a sealed tube for 15 hours. The reaction mixture was then cooled and concentrated in vacuo, and the residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (44 mg) as an off-white solid. LC-MS (ES) m/z=397 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17 (d, J=6.6 Hz, 3H), 2.22 (s, 6H), 2.35-2.45 (m, 2H), 2.66-2.80 (m, 1H), 2.84 (d, J=4.3 Hz, 3H), 3.49-3.60 (m, 1H), 3.66 (d, J=11.4 Hz, 1H), 3.75 (d, J=11.1 Hz, 1H), 4.02-4.79 (bs, 2H), 5.38 (s, 2H), 6.48-6.65 (m, 2H), 7.60 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: CN(C)C=O.[SH:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:10][N:11]=1.[OH-].[K+].[F:24][C:25]([F:29])=[C:26]([F:28])[F:27]>C(Cl)(Cl)Cl>[F:24][C:25]([F:29])([S:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[N:10][N:11]=1)[CH:26]([F:28])[F:27]
Reactant: FC(F)(F)c1cccc(-c2nnc(S)o2)c1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(F)C(F)(F)Sc1nnc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 60 °C

Procedure:
60 ml of dimethylformamide and 7.38 g of 2-mercapto-5-(3'-trifluoromethylphenyl)-1,3,4-oxadiazole (m.p. 154°-155° C.) and 0.7 g of potassium hydroxide are stirred in an autoclave. 22 g of tetrafluoroethylene are pressed in, and the reaction mixture is heated for 19 hours at 60° C. (10-12·105Pa). After cooling and release of pressure, the solution is poured into ice-water, the product is taken up in chloroform, the chloroform solution is washed with 1n sodium hydroxide solution, and the solvent is removed in vacuo, affording as reside the title compound in the form of an oil with a refractive index nD22 of 1.4926.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[CH3:21][C:22]1[C:26]([C:27](O)=O)=[C:25]([C:30]([F:33])([F:32])[F:31])[O:24][N:23]=1>>[CH3:21][C:22]1[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[C:25]([C:30]([F:32])([F:33])[F:31])[O:24][N:23]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Product: Cc1noc(C(F)(F)F)c1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-methyl-5-(trifluoromethyl)-4-isoxazolecarboxylic acid: MS (ESI): m/z 442 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1>C(Cl)Cl>[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1
Reactant: Cc1cc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 4-(5-methylthiophene-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 104, step a) (0.34 g) in DCM (10 mL) and the resulting mixture was stirred for 45 minutes and allowed to stand overnight. The solvent was evaporated in vacuo. Toluene (3×25 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in methanol (20 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (40 mL) and eluted with 2M ammonia in methanol solution (20 mL). The eluent was evaporated in vacuo to give the subtitled compound as a colourless oil. Yield 0.25 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7]2.CS(C)=O.S([O-])([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2
Reactant: OCc1ccc2cc(F)cc(Br)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc2cc(F)cc(Br)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(8-bromo-6-fluoroquinolin-2-yl)methanol (2 g, 7.8 mmol), DMSO (8.9 mL, 125.0 mmol), and TEA (4.9 mL, 35 mmol) were weighed into a flask and dissolved in a 10 mL of DCM, followed by cooling to 0° C. Pyridinium sulfate (4.351 g, 27.3 mmol) was added and the reaction stirred 0° C. for 1 hour. The reaction was poured onto 50 mL water and extracted with ethyl acetate. The combined organics were then dried over MgSO4, then concentrated in vacuo affording a yellow/white semi-solid, which was further purified by triturating with 20% ethyl acetate/Hexanes, affording the desired product as a tan solid (1.35 g, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[CH:7][CH:8]=1.[C:12](Cl)(=O)C(Cl)=O.CCl.[NH2:20][CH2:21][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:12][O:26][C:25](=[O:27])[CH2:24][CH2:23][C:22]([CH2:21][NH:20][C:9](=[O:11])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NCC(=O)CCC(=O)O
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)CNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 420.5 %

Procedure:
Under a nitrogen atmosphere, a catalytic amount of dimethylformamide was added to a solution of p-methoxybenzoic acid (5 g, 33.0 mmol) in dichloromethane (50 mL), and the obtained mixture was then cooled to 0° C. Thereafter, oxalyl chloride (5.8 mL, 66.1 mmol) was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, the solvent was distilled away, and the obtained residue was then added to a solution of 5-aminolevulinic acid methyl hydrochloride (1.0 g, 5.50 mmol) and triethylamine (2.3 mL, 16.5 mmol) in dichloromethane (80 mL) that had been cooled to 0° C. under a nitrogen atmosphere. The obtained mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was distilled away, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (6.46 g, yield: 84%).
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:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][N:35]=1.[C:44](=O)([O-])[O-].[K+].[K+].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.C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH2:41][CH3:44])=[O:39])=[CH:36][N: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: COC(=O)c1ccc(Br)nc1
Reactant: O=C([O-])[O-]
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
To a flask charged with 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) (800 mg, 1.850 mmol), methyl 6-bromonicotinate (440 mg, 2.036 mmol), potassium carbonate (767 mg, 5.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (214 mg, 0.185 mmol) were added toluene (8 mL) and ethanol (8 mL). The resulting mixture was stirred at 90° C. under nitrogen for 3 h at which point portions of potassium carbonate (384 mg) tetrakis(triphenylphosphine)palladium(0) (107 mg) and methyl 6-bromonicotinate (220 mg) were added and the reaction mixture stirring continued for 5 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography [25 g column, EtOAc/Hexanes gradient] to give ethyl 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (600 mg, 1.317 mmol, 71.2% yield) as a white foam. LCMS (HpH, 2 min), Rt=1.07 min, MH+=456.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][C:12]=2[CH3:22])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:30]1([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH2:31]1>C(O)C>[CH:30]1([CH2:33][N:34]([CH2:35][CH2:36][CH3:37])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH3:19])(=[O:21])=[O:20])=[CH:13][C:12]=3[CH3:22])=[O:9])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: CCCNCC1CC1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(2-methyl-4-(N-methylsulfamoyl)phenyl)pyrimidine-4-carboxamide (Intermediate 37, 80 mg; 0.235 mmol) and diisopropylamine (82 mL; 0.47 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml; 0.29 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[CH:17])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2].[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:29]=[CH:28][C:27](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:17]#[C:16][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]3[C:11](=[O:13])[CH2:10][CH2:9][C:8]([CH3:14])([CH3:15])[C:7]=3[CH:6]=2)=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: C#Cc1cc(CC)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C#Cc2ccc(C(C)(C)C(=O)OC)cc2)cc2c1C(=O)CCC2(C)C

Procedure:
Following General Procedure B and using 8-ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 180, 0.09 g, 0.39 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.152 g, 0.5 mmol), triethyl amine (8 mL), copper(I)iodide (0.024 g, 0.12 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.087 g, 0.12 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2-10% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.095 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[NH2:27][NH2:28]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][NH2:28])[C:5]([F:9])=[C:4]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: NN
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(Cl)nc(NN)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (402 mg, 2.0 mmol) in DMSO (3 mL) was added DIPEA (0.52 mL, 3.0 mmol), followed by N-methylpiperazine (0.24 mL, 2.2 mmol). The solution was stirred at room temperature. After 30 min, anhydrous hydrazine (1.29 mL, 99 mmol) was added, and the resulting mixture was heated at 80° C. for 30 min. After cooling to room temperature, the excess hydrazine was removed in vacuo, and the remaining solution was purified via RP-HPLC to provide the assumed 2-chloro-5-fluoro-4-hydrazino-6-(4-methyl-1-piperazinyl)pyrimidine (first eluent, 44 mg), as well as the assumed 6-chloro-5-fluoro-2-hydrazino-4-(4-methyl-1-piperazinyl)pyrimidine (second eluent, 30 mg). LCMS: (M+H)+: 261.1.
Reaction SMILES: CO[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([O:18][CH2:19][CH2:20]Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[SH:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.[CH2:47]([OH:49])C>>[CH3:47][O:49][CH:19]([O:18][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]1[CH:3]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:20][S:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:36][CH:37]=1
Reactant: COc1ccccc1C(OCCCl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCc1ccc(S)cc1
Reactant: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(CSc1ccc(CCC(=O)O)cc1)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
2-Chloroethyl monomethoxytrityl ether <1> (2.1172 g, 6 mmol) and 4-mercaptodihydrocinnamic acid <2> (0.9112 g, 5 mmol) were dissolved in ethanol (15 ml), and diisopropylethylamine (2.45 ml, 15 mmol) was added to the solution and the mixture was heated and refluxed for 12 hours. The solvent was removed by distillation under a reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.9945 g (yield=80%) of 4-(2-monomethoxytrityloxyethylthio)dihydrocinnamic acid <3> in the form of a syrup.