Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:31][CH2:32][O:33][CH3:34]>C(OCC)(=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1c(OC(=O)c2ccccc2)cccc1C(=O)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a mixture of methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate (21.2 g, 78 mmol), potassium carbonate (21.5 g, 156 mmol) and acetonitrile (370 mL) was added 1-bromo-2-(methyloxy)ethane (12.1 mL, 116 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (400 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (200 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide methyl 2-{[2-(methyloxy)ethyl]oxy}-3-[(phenylcarbonyl)oxy]benzoate, (22.5 g, 68 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): 8.25-8.23 (d, d, 2H), 7.76-7.74 (d, d, 1H), 7.68-7.64 (d, d, 1H), 7.55-7.51 (d, d, 2H), 7.40-7.38 (d, d, 1H), 7.23-7.19 (d, d, 1H), 4.17-4.15 (m, 2H), 3.92 (s, 3H), 3.58-3.55 (m, 2H), 3.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22](N)[N:21]=1.[OH-].[Na+].C[N:31](C=O)C>O.Cl>[Cl:19][C:20]1[N:21]=[C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[N:23]=[C:24]([NH2:31])[CH:25]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(Nc2ccc(Cc3ccnc4[nH]ccc34)c(F)c2)n1

Procedure:
40 mg (0.15 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)aniline and 29 mg (0.18 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 2 ml of water and 0.11 ml of 2N hydrochloric acid. The reaction mixture is heated at reflux for 15 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little DMF is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [CH:1]1([N:7]([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(S(N(C)CC(N(CC)CC)=O)(=O)=O)=CN=2)[CH2:6]CCC[CH2:2]1.[CH:36]1([N:42]([C@H:59]2[CH2:64][CH2:63][C@H:62](C)[CH2:61][CH2:60]2)[C:43](=[O:58])[NH:44][C:45]2[S:46][C:47]([S:50]([NH:53][CH2:54][C:55]([OH:57])=O)(=[O:52])=[O:51])=[CH:48][N:49]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[CH:66](N)(C)C>>[CH:36]1([N:42]([C@H:59]2[CH2:60][CH2:61][C@H:62]([CH3:66])[CH2:63][CH2:64]2)[C:43](=[O:58])[NH:44][C:45]2[S:46][C:47]([S:50]([NH:53][CH2:54][C:55]([NH:7][CH:1]([CH3:6])[CH3:2])=[O:57])(=[O:51])=[O:52])=[CH:48][N:49]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)N
Reactant: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Product: CC(C)NC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
The title compound was prepared in a similar manner to 2-({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide using {2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid and isopropylamine.
Reaction SMILES: C(O[C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])C.C(O[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](O)=O)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[OH:5][CH2:4][CH2:6][N:7]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([CH:43]2[CH2:44][CH2:45][N:40]([CH3:38])[CH2:41][CH2:42]2)=[CH:51][CH:50]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)c1
Yield: 45.1 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337,the title compound (18 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][O:16][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (0.61 g, 1.3 mmol) and N,N-diisopropylethylamine (0.37 g, 2.86 mmol) in anhydrous dichloromethane (12 mL). Cool the reaction mixture to 0° C. with an ice bath. Slowly add methanesulfonyl chloride (0.19 g, 1.7 mmol). After 3.5 hours, dilute the reaction mixture with dichloromethane and extract with 1M hydrochloric acid and with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.60 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]1(=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]1.C(=O)(OCC)OCC.Cl>C(O)C>[CH2:2]([CH:6]1[C:5](=[O:22])[N:20]2[C:21]3[C:12](=[CH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=42)[CH2:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)[CH3:3]
Reactant: O=C1CCC2=C3C(=Cc4ccccc4N13)CC=C2
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CCC1CC2=C3C(=Cc4ccccc4N3C1=O)CC=C2

Procedure:
To a freshly prepared solution of sodium ethoxide in ethanol (from 0.35 g sodium metal and 10 ml ethanol) was added 6H-pyrido[3,2,1-de]acridin-1(2H)-one (1.2 g) portionwise over a period of 10 minutes. To the resulting dark red solution was slowly added diethyl carbonate (1.77 g) and the solution was then refluxed for 3 hours. The reaction mixture was cooled, acidified to pH 2 with concentrated HCl and then extracted with methylene chloride. The organic extract was washed with water and was then collected, dried and evaporated to dryness to obtain a light amber solid (1.8 g; m.p. 113°-118° C.).
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:30]=[C:31]([Br:34])[CH:32]=[N:33][C:15]1=2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO.ClCCl>[CH2:4]([O:11][C:12]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:1][CH3:2])[CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:30]=[C:31]([Br:34])[CH:32]=[N:33][C:15]1=2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC=O
Reactant: O=C(OCc1ccccc1)n1c2cncc(OC3CCNCC3)c2c2cc(Br)cnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCN1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 61.3 %

Procedure:
Acetaldehyde (3M solution in dichloromethane, 0.16 mL, 0.48 mmol) was added to a mixture of 3-bromo-5-(piperidin-4-yloxy)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (116 mg, 0.24 mmol), sodium triacetoxyborohydride (77 mg, 0.36 mmol) and acetic acid (17 OL, 0.29 mmol) in methanol (3 mL) and dichloromethane (1 mL) and the mixture stirred for 18 hours. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was dried (Na2SO4), filtered and evaporated to give a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-8% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as a light yellow solid (75 mg, 61%). LCMS (Method B): RT=3.43 min, M+H+=509/511. 1H NMR (400 MHz, CDCl3): 9.23 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 7.60-7.60 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.85 (s, 1H), 2.91 (br s, 2H), 2.62 (br s, 2H), 2.33 (br s, 2H), 2.14 (br s, 2H), 1.59 (br s, 2H), 1.23 (br s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.I[CH2:26][C:27]#[N:28].[CH2:29]([O:36][C:37](=[O:69])[NH:38][C:39]1[N:68]=[C:42]2[N:43]([C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=3)[C:44]([CH3:57])=[C:45]([C:55]#[N:56])[C@@H:46]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=3)[N:41]2[N:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:69])[N:38]([C:39]1[N:68]=[C:42]2[N:43]([C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:65])[F:66])[CH:59]=3)[C:44]([CH3:57])=[C:45]([C:55]#[N:56])[C@@H:46]([C:47]3[CH:48]=[CH:49][C:50]([C:53]#[N:54])=[CH:51][CH:52]=3)[N:41]2[N:40]=1)[CH2:26][C:27]#[N:28])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: N#CCI
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC#N)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 mmol, 2.1 eq.), 18-crown-6 (30 mg, 113 mmol, 2.1 eq.) and iodoacetonitrile (19 mg, 113 mmol, 2.1 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 mmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 78% of theory).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH3:46][O:47][C:48]([C:50]1[O:51]C2C=CC(N)=CC=2[CH:54]=1)=[O:49]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][C:23]5[O:51][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:54][C:22]=5[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 8.13-8.10 (m, 2H), 7.63-7.54 (m, 3H), 7.27 (bs, 1H), 7.10 (d, 1H, J=8.7 Hz), 6.80 (d, 1H, J=8.1 Hz), 4.21 (s, 4H), 3.88 (s, 3H); LCMS: ret. time: 23.22 min.; purity: 95%; MS (m/e): 437 (MH+).
Reaction SMILES: [C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19](O)=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl.Cl>[C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19]([F:31])=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1(C(=O)O)CC2(C#N)c3ccccc3C1c1ccccc12
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C(=O)F)CC2(C#N)c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 9-cyano-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core A) (5.26 g, 18.2 mmol) and pyridine (2.2 mL, 27.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (2.14 g, 27.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 4.8 g (91%) of 9-cyano-9,10-dihydro-11-methyl-9,10-ethano-anthracene-11-carboxylic acid fluoride, Core B. MS found: (M+H)+=292.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:27]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:48]([O:52][C:53](=[O:56])[CH2:54]Br)([CH3:51])([CH3:50])[CH3:49]>C1COCC1.CN(C=O)C.C1COCC1>[C:48]([O:52][C:53](=[O:56])[CH2:54][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:47][CH:46]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: OCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To an ice-cooled suspension of sodium hydride (180 mg, 4.5 mmol; 60% in mineral oil) in THF/DMF (5/1 mixed solution 7 ml), a solution of Compound 24 (817 mg, 1.28 mmol) in THF (6 ml) was gradually added; this was followed by stirring for 30 minutes. A solution of bromoacetic acid tert-butyl ester (1.0 g, 5.1 mmol) in THF (7 ml) was added thereto. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, this was followed by extraction from ethyl acetate, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate solution containing 5% methanol)) to yield Compound 25 (light-yellow oil 655 mg, 68%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C(N(C(C)C)CC)(C)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(#N)C>[S:27]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[C:4]=2[CH:5]=[CH:6]1)([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a stirred solution of 4-Cyano indole (0.5 g, 3.5 mmol), diisopropylethylamine (1.8 mL, 10.5 mmol) in acetonitrile (5.0 mL), p-toluene sulfonyl chloride (0.8 g, 4.22 mmol) was added and the mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield the title compound as brown colored solid (0.95 g, 90%). [1H-NMR (CDCl3, 300 MHz): δ 8.22 (d, 1H), 7.81-7.72 (m, 3H), 7.56 (d, 1H), 7.38 (t, 1H), 7.29-7.22 (m, 2H), 6.88 (d, 1H), 2.39 (s, 3H)].
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11]C(C)=O>>[C:1]1([CH2:7][C:8](=[O:10])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: O=C(O)Cc1ccccc1
Product: CC(=O)Cc1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid is phenylacetic acid to yield phenylacetone.
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]([F:15])([F:14])[C:5](O[C:8](=[O:13])[C:9]([F:12])([F:11])[Cl:10])=[O:6].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>COCCOCCOC>[C:18]([C:8]([C:9]([Cl:10])([F:11])[F:12])=[O:13])([C:19]([F:1])([F:21])[F:20])([C:17]([F:24])([F:23])[F:16])[F:22].[Cl:3][C:4]([F:15])([F:14])[C:5](=[O:6])[C:18]([F:22])([C:19]([F:1])([F:21])[F:20])[C:17]([F:24])([F:23])[F:16]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: [F-]
Reactant: O=C(OC(=O)C(F)(F)Cl)C(F)(F)Cl
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(F)Cl)C(F)(C(F)(F)F)C(F)(F)F
Yield: 78 %

Procedure:
To a clean dry 600 mL Parr pressure reactor was charged 53.5 g (0.92 mol) of anhydrous potassium fluoride, 150 g of anhydrous diglyme and 150 g of chlorodifluoroacetic anhydride. With the reactor set at 80° C. and 92 psig (5500 torr), 123 g (0.820 mol) of hexafluoropropylene was charged over a 3 hour period at a tank pressure not exceeding 120 psig (7000 torr). Following reaction for ½ hour at 80° C., the reactor contents were allowed to cool and were distilled to obtain 180.6 g of crude material. Upon fractional distillation, acetic acid/KMnO4 treatment and refractionation of the crude material, 46.1 g (26% of theoretical yield) of (CF3)2CFC(O)CF2Cl, a clear colorless liquid, was obtained having a purity of 98.8% as determined by gas chromatography.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:18]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[N:19]=1.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCCCCCCCn1ccnc1
Agent: Cl
Agent: I
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.1 of 8-(1H-imidazol-l-yl)octanamine, 400 ml of ethanol, and 3.2 g of 2-(methylthio)benz(cd)indole hydriodide was reacted as described in Example 19, giving the base derivative which was then treated with hydrochloric acid giving 1.3 g of the desired hydrochloride salt, mp 222° C.-224° C.
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].[NH2:34][CH2:35][CH2:36][OH:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:37][CH2:36][CH2:35][NH:34][C:30]([C:26]1[CH:25]=[C:24]2[C:4]3([CH2:5][CH2:6][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:9]3)[C:3](=[O:33])[N:2]([CH3:1])[C:29]2=[CH:28][CH:27]=1)=[O:32]
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)NCCO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.04 mmol) in anhydrous CH2Cl2 (5 mL) was added 2-aminoethanol (3.6 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) at 0° C. and the mixture was stirred overnight at rt under N2. The reaction mixture was washed with 1 N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by prep TLC to give (E)-N-(2-hydroxyethyl)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (8 mg, 40%). 1H NMR (CD3OD): 1.90 (m, 4H), 3.25 (s, 3H), 3.50 (m, 2H), 3.70 (m, 2H), 3.98 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.53 (m, 1H), 7.68 (m, 1H), 7.75 (m, 1H), 7.90 (m, 2H), 8.00 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCO.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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cccc(F)c2)cc1C(=O)O
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (1 g, 5.12 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (720 mg, 4.65 mmol, 1.1 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and H2O (5 mL) were added Na2CO3 (1.98 g, 18.68 mmol, 4 eq) and Pd(PPh3)4 (270 mg, 0.23 mmol, 0.05 eq). The mixture was heated at 100° C. under N2 for 4 h and the reaction quenched by addition of 1M HCl. The aqueous phase was extracted with EtOAc and the combined organic extracts washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether:EtOAc, 20:1 to 1:1) to give the title compound as a white solid (780 mg, 68%).