Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>C(#N)C>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: COCCl
Reactant: O=c1ccc2cc(O)ccc2o1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2oc(=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution, Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetatefleptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4cc(C(F)(F)F)ccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-4-trifluoromethyl-pyridine at 120° C.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[N+:27]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.5 parts of 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazineethanamine in 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Ra/Ni. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding N1 -{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine as an oily residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
To a suspension of 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature for 24 h. The mixture was poured onto 30 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to provide the crude product which was purified by silica gel flash chromatography to afford the title product (68 mg, 25%); LCMS; 95%; APCI+, Calcd 493.05. Found m/z 493.2 (M). 1H NMR (400 MHz, CDCL3); δ 1.47 (d, J=5.6 Hz, 3H), 1.52-2.01 (m, 6H), 2.21-2.59 (m, 4H), 2.79-2.98 (m, 2H), 3.12-3.23 (m, 1H), 3.68-3.89 (m, 2H), 5.10-5.17 (m, 1H), 6.81 (d, J=9.2 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 7.22-7.26 (m, 5H), 7.29 (d, J=4.4 Hz, 2H).
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10](Br)=[CH:9][N:8]=1.N1(C=O)CC[O:18][CH2:17]C1.O>C1COCC1>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:17]=[O:18])=[CH:9][N:8]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: O=CN1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)cnc1Br
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to −78° C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0° C. over 30 minutes, followed by stirring at 0° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]2.[CH3:25][S:26]SC.Cl>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[C:17]([S:26][CH3:25])=[CH:16]2
Reactant: Cc1ccc2cc(C=O)ccc2c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1cc2cc(C)ccc2cc1C=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
A 200 ml three-neck flask equipped with a dropping funnel was heated and dried, and air in the flask was replaced with nitrogen. N,N,N′-trimethyldiamine (1.22 ml, 9.6 mmol) and anhydrous THF (40 ml) were added into the flask and cooled down to −30° C. A butyllithium hexane solution (1.57 M, 6.14 ml, 9.6 mmol) was added thereto and stirred for 15 minutes. The temperature in the flask was brought back to −20° C., and an anhydrous THF (40 ml) solution of 6-methyl-2-naphthaldehyde (1.0 g, 5.9 mmol) was slowly dropped therein and stirred for 15 minutes. Further, after a butyllithium hexane solution (1.57 M, 11.2 ml, 0.017 mol) was added therein and stirred for 3.5 hours, dimethyldisulfide (2.6 ml, 0.029 mol) was added. The temperature was increased to a room temperature, and an obtained solution was stirred for 2 hours. Then, 1 M hydrogen chloride was added to stop the reaction, an obtained reaction solution was extracted with methylene chloride, and an organic layer was dried with anhydrous magnesium and filtrated. A filtrate was concentrated by use of a rotary evaporator. A residue was purified by silica gel column chromatography by use of a mixture solvent of hexane and ethyl acetate (hexane:ethyl acetate=9:1) as a mobile phase, so as to obtain 6-methyl-3-methylthio-2-naphthaldehyde (386 mg, 1.8 mmol, 30%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(SC)c2ccc(Cl)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm;
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[Mg].II.[Br-].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17]Br>C1COCC1.II>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: BrCCC1OCCCO1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCCC2OCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxane (3.41 ml, 4.88 g, 25.0 mmol) in dry THF (15 ml) was slowly added to dry magnesium turnings (0.67 g, 27.5 mmol) and ~10 mg iodine at room temperature under N2. After heat evolved and the iodine color vanished, the contents were heated to reflux and the remainder of the bromide solution was added dropwise over 10 min. After 2 h reflux, the alkylmagnesium-bromide solution was cooled to room temperature and transferred via syringe to a solution of 2-bromo-5-methoxybenzyl bromide (3.50 g, 12.5 mmol) in 20 ml dry THF. The contents were cooled to -10° with ice-salt, treated with Li2 CuCl4 in THF (0.45 ml of 0.1M solution), and allowed to stir at room temperature overnight for convenience. After 19 h, the solvent was evaporated and the residue partitioned between ether and 5% NH4Cl. The ether layer was washed with 5% NH4Cl, water, and brine, then dried over MgSO4, filtered, and evaporated to yield 4.59 g of a pale yellow oil. The crude material was purified by column chromatography (140 g silica gel, 50% ether/petroleum ether as eluent) under "flash" conditions to yield 2.31 gm (58%) of the dioxane as a colorless oil; tlc (silica gel, 50% ether/petroleum ether) Rf 0.48. A dimeric by-product, 1,2-bis(2-bromo-5-methoxyphenyl)ethane, was obtained as a white solid (1.02 g, 41%); mp 98°-101°. TLC (silica gel, 50% ether/petroleum ether) Rf 0.63.
Reaction SMILES: [NH:1]1C2C(=CC=C(C#N)C=2)C=[CH:2]1.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OC(F)(F)F)[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]#[N:1])=[CH:21][CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: N#Cc1ccc2cc[nH]c2c1
Product: CC(=O)c1cn(CC(=O)O)c2cc(C#N)ccc12

Procedure:
was prepared from 1H-indole-6-carbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 243 [M+H]+; tR (HPLC conditions k): 2.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClS([N:21]=[C:22]=[O:23])(=O)=O.O>C(OCC)(=O)C>[NH2:21][C:22]([N:13]1[CH2:14][CH2:15][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:12]1=[O:16])=[O:23]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(N2CCNC2=O)cc1OC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(C(N)=O)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 13.33 g (60 mmol) of 1-(3,4-dimethoxyphenyl)-2-imidazolidinone in 150 ml of ethyl acetate was cooled to 0° C., and 8.92 g (63 mmol) of chlorosulfonylisocyanate was added dropwise. The mixture was stirred for one hour at room temperature. To the resulting thick suspension was added 50 ml of water, and the mixture was stirred until two clear layers were formed. The aqueous phase was separated and stored in the refrigerator overnight. The precipitate was filtered off by suction, washed with water and dried in vacuo; yield: 11.04 g; melting point 240° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[CH:11][C:10]2[C:13]3([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH:14]3[CH2:15][CH2:16][CH2:17][C:9]=2[CH:8]=1)(=O)=O.[CH:35](/B(O)O)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][C@@:13]12[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C:9]1[CH:8]=[C:7](/[CH:35]=[CH:36]/[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:12]=[CH:11][C:10]=12
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=S(=O)(Oc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C(=C/c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3)\c1ccccc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
A flask with stir bar and nitrogen line was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl trifluoromethanesulfonate (144, R2=Pyridin-2-ylmethyl) (9.14 g, 18.34 mmol) (assumed 100% for previous reaction), (E)-styrylboronic acid (3.39 g, 22.9 mmol), cesium carbonate (14.94 g, 45.9 mmol), 1,4-dioxane (130 mL), water (32.5 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.644 g, 0.917 mmol). The mixture was warmed in an oil bath heated to about 90° C. for about 30 min. The mixture was cooled then concentrated under reduced pressure. The material was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated then the organic solution was washed with brine (75 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using 100% EtOAc. Product fractions were combined and concentrated under reduced pressure to yield (7aR,11aS)-11a-(pyridin-2-ylmethyl)-3-((E)-styryl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane] (145, R2=Pyridin-2-ylmethyl) (6.15 g, 74%); LC/MS, method 3, Rt=2.50 min, MS m/z 453 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.59-7.52 (m, 3H), 7.38-7.35 (m, 2H), 7.33-7.05 (m, 4H), 6.97-6.94 (m, 1H), 6.23 (s, 1H), 4.04-3.90 (m, 4H), 3.49 (d, J=13.8 Hz, 1H), 3.39-3.29 (m, 1H), 3.25 (d, J=13.3 Hz, 1H), 2.97-2.89 (m, 1H), 2.28-2.20 (m, 1H), 2.11-1.96 (m, 4H), 1.92-1.86 (m, 1H), 1.84-1.70 (m, 2H), 1.69-1.48 (m, 3H).
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2.C(#N)C.Cl[C:18]1[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=1.Cl>C(OCC)(=O)C.[Fe]>[C:1]12([C:12]3[CH:11]=[C:10]([O:13][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=4)[CH:9]=[CH:8][C:7]=3[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Oc1ccc2c(c1)C1(CCC1)OC2
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1cnc(Oc2ccc3c(c2)C2(CCC2)OC3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a solution of spiro[1H-isobenzofuran-3,1′-cyclobutane]-5-ol (Intermediate 24, 50 mg, 0.28 mmol) in dry acetonitrile (4 mL) dipotassium carbonate (58.8 mg, 0.43 mmol) and then 2-chloro-5-nitro-pyrimidine (43.0 mg, 0.27 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was diluted with ethyl acetate (20 ml) and washed with an aqueous saturated solution of ammonium chloride (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (5 mL)/water (1 mL). Iron (95.0 mg, 1.7 mmol) and an aqueous 6M solution of hydrogen chloride (0.05 ml, 0.3 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (10 ml) and extracted with ethyl acetate (2×15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 60:40 to 0:100 as eluent affording the title compound (24 mg) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:41]([C:38]2([C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[O:37])[CH2:40][CH2:39]2)=[O:42])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:24])[CH:8]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 41.6 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg), triethylamine (0.0456 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg) were added under a nitrogen atmosphere at room temperature and stirred for 3.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the titled compound as white powder (26.3 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]([CH3:14])[CH3:15])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
This crude methyl [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethyl-amino)pyrimidin-5-yl]acetate was dissolved in THF (3 mL) and treated with 1N NaOH (2 mL) and stirred at room temperature for 24 hour. Et2O was added and the organic phase was siphoned off. The remaining aqueous layer was acidified with 6N HCl to pH˜5 and the separated solids were collected by suction and rinsed with water and diisopropyl ether. Drying under high vacuum at room temperature for 4 hours then gave [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]-benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetic acid (0.029 g, 27% yield) as a pale yellow powder.