Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([CH:60]([CH3:62])[CH3:61])[CH:54]=1)[C:46]([OH:48])=[O:47]>CO.C(Cl)Cl>[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:54]=[C:55]([CH:60]([CH3:61])[CH3:62])[C:56]([OH:59])=[C:57]([Br:1])[CH:58]=1)[C:46]([OH:48])=[O:47]
Reactant: [Br-]
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2ccc(O)c(C(C)C)c2)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Yield: 32.7 %

Procedure:
A suspension of benzyltrimethylamonium tribromide (2.2 g, 5.63 mmol) and CaCO3 (0.28 g, 2.82 mmol) was stirred for 2 hr at 20° C. in a 1:1 MeOH/CH2Cl2 solution (10 mL) containing 3,5-dichloro-2-methyl-4-(4-hydroxy-3-isopropylphenoxy)-benzoic acid (1.0 g, 2.82 mmol). Once HPLC analysis indicated that conversion to the desired monobrominated phenol was optimal, the reaction was quenched by addition of 15 mL of 1N HCl. After removal of the organic solvents under vacuum using a rotary evaporator, the aqueous suspension was extracted twice with EtOAc. After drying the combined EtOAc layers over MgSO4, the salts were filtered prior to removal of the EtOAc under vacuum. The resulting residue after purification by gradient elution from a reverse phase C18 column employing MeOH/H2O containing 0.1% TFA yielded 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (400 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15].[CH3:16]I.O>CN(C)C=O>[CH3:16][N:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15]
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n2c3c(cccc31)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.36 g) was added to a solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10 g) obtained in Reference Example 131 in dimethylformamide (100 ml), the mixture was stirred at room temperature for 1 hour, methyl iodide (3.68 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water (200 g) was poured into the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow solid (9.7 g). Further recrystallization from water-ethyl acetate afforded the title compound as colorless crystals (9.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate(140 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:17].[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH2:25].C1C=CC2N(O)N=NC=2C=1.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CCN=C=NCCCN(C)C>ClCCl.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH:25][C:8](=[O:10])[CH:7]([CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[C:3]([CH3:17])[CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NOC1CCCCO1
Reactant: CCCCC(Cc1ccc(F)c(C)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 64 h
Yield: 60 %

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (0.498 g, 2.091 mmol), O-(tetrahydro-pyran-2-yl)-hydroxylamine (0.735 g, 6.274 mmol), HOBT (0.282 g, 2.091 mmol), and N-methyl morphine (1.058 g, 10.455 mmol) in 20 mL of dichloromethane, was added EDCI (0.601 g, 3.137 mmol). After stirring at room temperature under N2 for 64 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4. After removing the solvents under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-40% ethyl acetate/hexanes to give the title compound as a pale yellow solid (0.423 g, 60% yield). LC-MS: tR=9.1 min; m/z 338 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][O:13][C:11]2[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC1CC1

Procedure:
F1 was prepared from D1 following the general procedure reported in Preparative Example 16 Step 2 using (bromomethyl)cyclopropane for the alkylation. MS (ES) C16H17FN2O3 requires: 304. Found: 305 (M+H)+ and 327 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C1(C(C)[CH:18]=[O:19])C=CC=CC=1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:18]=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C=O)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CC=O)cc1

Procedure:
This compound was prepared from 4-cyanobenzaldehyde using a modification of a procedure previously used in the multi-step synthesis of 2-phenylpropanal {Allen, C. F. H.; van Allan, J., Org. Syn. Coll. Vol 3, 733-734 (1955)}.
Reaction SMILES: C([O:3][C:4](OCC)(OCC)[O:5]CC)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:32])[CH2:29][Mg]Br)=[CH:24][CH:23]=1.BrCC(C1C=CC(C2C=CC(F)=CC=2F)=CC=1)C.Cl>C1COCC1>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:32])[CH2:29][C:4]([OH:5])=[O:3])=[CH:24][CH:23]=1
Reactant: CC(C[Mg]Br)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CCOC(OCC)(OCC)OCC
Agent: CC(CBr)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2 g. of orthocarbonic acid tetraethyl ester are added to a solution of 2-(2',4'-difluoro-4-biphenylyl)-1-propylmagnesium -bromide, prepared from 3.11 g. of 4-(1-bromo-2-propyl)-2',4'-difluorobiphenyl, in 40 ml. of THF and the mixture is stirred for 4 hours at 25°. Excess dilute hydrochloric acid is added slowly. The mixture is heated under reflux for 24 hours, allowed to cool and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47])C.[Cl:49]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:49][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2ccccc2)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3ccccc3)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of 2.75 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(phenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 25 ml of dry chloroform at -40° C. was added a solution of 5.3 mmol of chlorine in 7 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound (1.98 g)
Reaction SMILES: [N+]([C:4]1[C:21]2[C:20](=[O:22])[C:19]3[C:10](=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9](=[O:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[O:36]([C:4]1[C:21]2[C:20](=[O:22])[C:19]3[C:10](=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9](=[O:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2c(Oc3ccccc3)cccc21

Procedure:
3 g (9.9 mmol) of 1-nitronaphthacene-5,12-dione (Example 42), 2.73 g (19.8 mmol) of potassium carbonate, 1.39 g (14.8 mmol) of phenol and 30 ml of DMSO are stirred at a bath temperature of 100° C. for 6 hours. After cooling, the mixture is partitioned between methylene chloride/dilute hydrochloric acid. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated. The product is obtained in a pure form by chromatography on silica gel (mobile phase: methylene chloride); yield 2.52 g (73%); melting point 195°-200° C.
Reaction SMILES: [OH-:1].[K+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]#[N:21])[CH2:5][CH2:4]1>C(O)(C)(C)C.C(O)C>[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]([NH2:21])=[O:1])[CH2:5][CH2:4]1
Reactant: N#Cc1c(OC2CCCNCC2)ccc2[nH]ncc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: NC(=O)c1c(OC2CCCNCC2)ccc2[nH]ncc12
Reaction time: 30 h
Yield: 25.3 %

Procedure:
Potassium hydroxide (powder, 100 mg) was added to a solution of the 5-(azepan-4-yloxy)-1H-indazole-4-carbonitrile (9.2 mg, 0.036 mmol) obtained in Example 691 in t-butanol (2 ml) at room temperature, and the resulting mixture was stirred for 30 hours with heating under reflux while maintaining the temperature. The reaction mixture was diluted with ethanol and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/28% aqueous ammonia) to obtain 5-(azepan-4-yloxy)-1H-indazole-4-carboxamide (2.5 mg, 25%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[Cl:39][CH2:40][C:41]1[C:42]([CH3:47])=[N:43][O:44][C:45]=1[CH3:46].Cl>CN(C=O)C.CCOCC>[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:40][C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1noc(C)c1CCl
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2c(C)noc2C)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 24 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (1.00 g, 2.281 mmol) in DMF (10 mL) is added K2CO3 (1.580 g, 0.011 moles). After stirring for 15 minutes 4-chloromethyl-3,5-dimethylisoxazole (0.35 g, 2.39 mmol) is added. The mixture is stirred for 24 hours. The solvents were removed under high vacuum. After diluting with ethyl acetate and washing with water and brine the solution is dried over MgSO4. Evaporation in vacuo affords a viscous oil which is dissolved in ether and treated with ethereal HCl to afford a foamy solid upon evaporation in vacuo. This solid is crystallized from ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[NH:31])OCC)=[CH:22][CH:21]=1>C(O)C>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=N)Cc1ccc(OC)cc1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(=N)Nc2ncccc2OCc2ccc(F)cc2)cc1
Yield: 14.9 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl 4-methoxyphenylacetimidate hydrochloride (5.04 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil, which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic gum (1.2 g), m.p. 199°-200° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].CS(C)=O.[CH2:26]1[O:34][CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[C:28]1([CH:27]([OH:34])[CH2:26][O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: OC(COCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer was separated and mixed with 10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxy]ethanol (compound No. 144).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.O>[CH2:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1NC(=O)C2CC12
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCN1C(=O)C2CC2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.48 g, 60% in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (4.0 g) and 1-iodooctane (8.88 g) in dry dimethylformamide (70 ml) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for a further 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water (100 ml) and then extracted with ether (150 ml). The organic extract was washed with water (2×70 ml), dried (MgSO4) and evaporated in vacuo to leave a brown oil. The oil was purified by distillation in vacuo (boiling point 146-147° C. @ 0.1 mmHg) to give the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.O=S(Cl)Cl.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[N:3]=[C:4]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Nc1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(N)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-6-pyridinecarboxylic acid (90; 6.0 g, 43.5 mmol) in ethanol (150 mL) was added SOCl2 (12.0 g, 101 mmol) at 0° C. The resulting reaction mixture was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Enough saturated aqueous Na2CO3 solution was added to adjust the pH=9. The mixture was concentrated under reduced pressure and dichloromethane (150 mL) was added to the resulting residue. The mixture was stirred vigorously at room temperature for 30 min and then filtered. The filtrate was concentrated under reduced pressure to afford ethyl 6-aminopicolinate 91 (5.5 g, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([OH:20])=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([CH2:64][N:65]3[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]3)[CH2:61][C:60]=2[CH:71]=1>ClCCl>[O:20]=[C:18]([N:68]1[CH2:69][CH2:70][N:65]([CH2:64][CH:62]2[CH2:61][C:60]3[CH:71]=[C:56]([C:55]([F:73])([F:54])[F:72])[CH:57]=[CH:58][C:59]=3[O:63]2)[CH2:66][CH2:67]1)[CH2:17][O:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)O)CC2)cc1C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(CC4Cc5cc(C(F)(F)F)ccc5O4)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.29 mmol) in dichloromethane (30 ml) was added EDAC.HCl (84.2 mg, 0.44 mmol, 1.5 eq), HOBt (59.2 mg, 0.44 mmol, 1.5 eq), triethylamine (59.1 mg, 0.58 mmol, 2 eq) and 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine (92.0 mg, 0.32 mmol, 1.1 eq). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water (30 ml). The crude product was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by Pre-TLC with 20% ethyl acetate in dichloromethane to afford 4-([4-[2-oxo-2-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethoxy]cyclohexyl]amino)-2-(trifluoromethyl)benzonitrile as a white solid (76 mg, 43%); (ES, m/z): [M+H]+ 611.30; 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 6.81-6.86 (m, 2H), 6.64-6.68 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.29 (d, J=7.8 Hz, 1H), 4.21 (s, 2H), 3.65-3.78 (m, 3H), 3.30-3.48 (m, 3H), 3.01-3.06 (dd, J=8.4 Hz, 15.9 Hz, 2H), 2.51-2.90 (m, 4H), 2.10-2.19 (m, 4H), 1.44-1.58 (m, 3H), 1.21-1.33 (m, 3H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].I[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[C:2][CH2:3][CH2:4][CH3:5]
Reactant: C#CCCC
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1ccccc1C(=O)OC
Yield: 101 %

Procedure:
Pent-1-yne (5.6 mL, 57.2 mmol) was added to methyl 2-iodobenzoate (5.6 mL, 38.2 mmol), copper(I) iodide (1.0 g, 5.72 mmol) and Pd(PPh3)4 (1.3 g, 1.14 mmol) in DMF (5 mL) and Et3N (1 mL) at RT for 3 hrs. The reaction was partitioned between Et2O and 0.1 M HClaqueous. The resulting organic phase was washed with 0.1 M HClaqueous, NaHCO3aqueous and brine. Organic phase was then anhydrified over Na2SO4 and dried under reduced pressure to give methyl 2-(pent-1-ynyl)benzoate (7.8 g) as a dark oil. The crude will be used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:47])/[C:32](/[C:45]#[N:46])=[CH:33]/[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:37][C:34]([CH3:36])([CH3:35])[CH:33]=[C:32]([C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[F:24])=[N:9]1)=[O:47])[C:45]#[N:46]
Reactant: CC(C)(/C=C(\C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R,E)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate (90 mg, 0.14 mmol, 1 equiv) in 16 mL DCM was added 4 mL trifluoroacetic acid dropwise. The resulting solution was stirred for 3 h at room temperature. The solution was concentrated under reduced pressure. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm to give the title compound as a pale light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:7]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=2[C:9](O)=[O:10])=O)[CH2:3][CH2:2]1.O.[NH2:19][NH2:20]>>[CH:1]1([CH2:4][C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)CC2CC2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(CC3CC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(2-cyclopropylacetyl)-5-methoxybenzoic acid with hydrazine hydrate.