Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][CH:34]([CH3:38])[CH2:35][O:36][CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][CH:34]([CH3:38])[CH2:35][O:36][CH3:37])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: COCC(C)N
Product: COCC(C)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-1-methoxy-propane (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2450.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>B(F)(F)F>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 90 °C

Procedure:
Resorcinol (4.4 g, 40 mmol) and 4-methoxyphenylacetic acid (6.6 g, 40 mmol) in boron trifluoride.etherate (25 ml, 0.2 mol) was heated, under a nitrogen atmosphere, at 90° C. for ˜90 mins. to give a pale red solution. The solution was allowed to cool and poured into aqueous sodium acetate (200 ml, 10%) and the mixture stirred to give a pale yellow precipitate. The solids were removed by filtration and washed with water (200 ml). Solids were taken up in ethyl acetate (250 ml) and washed with water (200 ml). Solution was dried over anhyrous magnesium sulphate and concentrated, to a yellow semi-solid. Trituration with diethyl ether (100 ml) gave the 1-(2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone as a pale orange solid, dried in vacuo, (2.2 g) LC retention time 2.39 minutes [M+H]+ 259.2 (Run time 3.75 mins) N.M.R (DMSO-d6) 7.95(d J 8.9 Hz ArH) 7.2(d J 8.7 Hz 2ArH) 6.9(d J 8.7 Hz 2ArH) 6.4(d J 9.9 ArH) 6.25(s ArH) 4.2(s 2CH2) 3.75(s 3OCH3)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:22]4[CH:23]=[CH:24][C:25]([O:27]C)=[CH:26][C:21]=4[S:20][N:19]=3)=[O:17])=[CH:11][C:10]=2[C:29]([F:32])([F:31])[F:30])[CH2:4][CH2:3]1.B(Br)(Br)Br.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:22]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=4[S:20][N:19]=3)=[O:17])=[CH:11][C:10]=2[C:29]([F:32])([F:30])[F:31])[CH2:4][CH2:3]1
Reactant: COc1ccc2c(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)nsc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(O)ccc34)cc2C(F)(F)F)CC1

Procedure:
1.923 g (4.14 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide in 120 ml of a 1 M solution of BBr3 in CH2Cl2 are stirred for 16 h at 45° C. Then the solution is poured into water and EtOAc, the aq. layer is neutralized with Na2CO3, separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Reversed phase chromatography (Gilson system) gives the title compound: MS: [M−1]=451; HPLC: tRet=11.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Si:16]([O:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CC=CC=1>ClCCl.C(O[Cu]OC(=O)C)(=O)C>[Si:16]([O:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH:29]=1)([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]cn1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-n2cnc(CO[Si](C)(C)C(C)(C)C)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (1.56 g) and 4-(tert-butyldimethylsilyloxymethyl)imidazole (1.26 g) were dissolved in dichloromethane (10 mL), and to the solution pyridine (562 mg) was added. Bisacetoxycopper (1.29 g) was then added to the mixture, and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[C:14]2[C:10](=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.O>CS(C)=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:11]1[O:12][N:13]=[C:14]2[C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: [C-]#N
Reactant: Clc1ccc(-c2onc3c(CBr)cccc23)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3Cl)onc12
Reaction time: 8 h
Yield: 33 %

Procedure:
To a slurry of 1.8 g (0.028 mole) of potassium cyanide in 80 ml of dimethylsulfoxide at 60° C. was added 9.7 g (0.027 mole) of 7-(bromomethyl)-3-(2,4-dichlorophenyl)-2,1-benzisoxazole. The mixture was heated at 50°-60° C. for 3 hr, poured into 1 liter of water and let stand overnight. The resulting solid was collected by filtration, washed with water and dried to give 7.6 g of crude tan solid. The solid was chromatographed on 160 g of silica gel to give 2.7 g of solid. The solid was recrystallized from carbon tetrachloride (charcoal) and then from acetonitrile to yield 0.7 g (8%) of crystals, m.p. 147°-148° C.
Reaction SMILES: [Br:1]C1C=C(C2C(C(Cl)=O)=CC=CC=2)[ClH]C=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[C:24]1[C:29]([C:30]2[NH:31][CH:32]=[C:33]([CH3:35])[N:34]=2)=[CH:28][N:27]=[C:26]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:25]=1>>[Br:1][C:21]1[CH:20]=[CH:19][C:18]([C:24]2[C:29]([C:30]3[NH:31][CH:32]=[C:33]([CH3:35])[N:34]=3)=[CH:28][N:27]=[C:26]([NH:36][CH2:37][CH2:38][NH:39][C:40]3[N:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[N:25]=2)=[C:17]([Cl:16])[CH:22]=1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Br)cc2Cl)n1

Procedure:
6-[(2-{[4-(4-bromo-2-chlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-bromo-2-chlorolbenzoyl chloride using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino)ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:20]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([O:11][CH3:20])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)O)c1cccc(Br)c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoic acid (11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL) followed by TMSCHN2 (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixture was stirred at RT for 16 h. Solvents were evaporated and the residue was chromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g (100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate as a yellow oil. 1H NMR (CDCl3) 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H), 1.36 (br s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=O)[CH:5]=[CH:4][C:3]1=2.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(F)cc3)ccc21
Yield: 60.7 %

Procedure:
In a manner analogous to Example 1, 2 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxylic acid and 1 g of 4-fluoroaniline were used to obtain 1.7 g of 4'-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxanilide in colorless crystals, m.p. 163°-165° C. (from ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:49][C@@H:50]1[CH2:55][NH:54][CH2:53][C@H:52]([CH3:56])[NH:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:53][C@H:52]([CH3:56])[NH:51][C@H:50]([CH3:49])[CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (40 mg, 0.062 mmol), (2R,6S)-2,6-dimethylpiperazine (70.73 mg, 0.619 mmol, 10 eq) and acetic acid (3.55 μL, 0.062 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in a VX-2500 Multi-Tube Vortexer overnight at room temperature. MP-triacetoxyborohydride (195 mg, 0.482 mmol, 7.78 eq) was then added and the mixture was stirred again in the VX-2500 Multi-Tube Vortexer overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on a Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 11.3 mg (27.2%) of the title compound. LC-MS m/z 744 (M+H)+, 1.41 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[CH:7]=[O:8].C1C(=O)N([Br:16])C(=O)C1>C1COCC1>[Br:16][C:6]1[C:2]([CH3:1])=[C:3]([CH:7]=[O:8])[NH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc[nH]c1C=O
Solvent: C1CCOC1
Product: Cc1c(Br)c[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Following a general procedure,50 a stirred solution of 3-methyl-pyrrole-2-carboxaldehyde (2, 5.63 g, 51.6 mmol) in THF (52 mL) was cooled to 0° C. NBS (9.19 g, 51.6 mmol; reagent grade, unrecrystallized) was added all at once. The reaction mixture was stirred for 15 min at 0° C. under argon before the solvent was removed on a rotary evaporator. The resulting solid was dried under high vacuum for 2 h. Water (100 mL, room temperature) was added to the flask and the suspension was filtered (Büchner funnel). The filter cake was washed with an additional 100 mL of water. The solid filtered material was recrystallized from water/ethanol as follows. The solid filtered material was transferred to a 250 mL round bottom flask equipped with a reflux condenser. Water/ethanol (150 mL, 5:1) were added and the mixture was refluxed in a hot water bath until all solid material had dissolved. Upon allowing the solution to cool to room temperature the product crystallized. The mixture was cooled to 4° C. for 2 h to promote more crystallization. The mixture was vacuum-filtered and the resulting off-white crystals were dried under high vacuum for 24 h (7.78 g, 80%): mp 140-143° C.; 1H NMR δ 2.32 (s, 3H), 7.08 (d, J=3.3 Hz, 1H), 9.60 (s, 1H), 9.95 (brs, 1H); 13C NMR δ 9.8, 101.7, 126.0, 129.3, 131.7, 177.9; ESI-MS obsd 187.9708, calcd 187.9706 [(M+H)+, M=C6H6BrNO].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][C:4]([NH:6][C:7]1([C:10]([O-:12])=[O:11])[CH2:9][CH2:8]1)=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:1][C:2]([F:13])([F:14])[CH2:3][C:4]([NH:6][C:7]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)=[O:5]
Reactant: O=C(CC(F)(F)F)NC1(C(=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(F)(F)F)NC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-Butyl (±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)-amino]cyclopropane carboxylate (489 mg, 1.44 mmol) was dissolved in a mixture of 4 mL of methylene chloride and 1.22 mL of trifluoroacetic acid. The reaction mixture was allowed to stir at ambient temperature for 3.5 hours. The solvents were removed in vacuo and the residue was azeotroped with toluene (450 ml) to afford 408 mg of (±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]cyclopropane-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[C:17](=[O:20])([O-:19])[O-].[K+].[K+].[I-].[K+].[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29]>C(#N)C>[C:27]([OH:33])(=[O:26])[C:17]([OH:19])=[O:20].[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Product: O=C(O)C(=O)O
Temperature: 42.5 °C
Reaction time: 3.5 h

Procedure:
100 g 4-Bromomethyl-2′-cyanobiphenyl is added to 500 ml acetonitrile followed by 69 g of anhydrous potassium carbonate, 12 g potassium iodide and 65 g L-Valine methyl ester. The reaction mixture is stirred at 40-45° C. for 3-4 hours. After completion of the reaction, the reaction mixture is filtered and acetonitrile is removed under vacuum at 45-50° C. 300 ml of water and 300 ml of o-xylene are added to the residue and the layers are separated. Solution of 50 g oxalic acid in 500 ml water is added to the organic layer and stirred for about an hour and filtered. The solid is washed and then dried under vacuum at 50-55° C. (yield: 130-135 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[O:1][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[N:7]=1
Reactant: COc1ccccc1CN
Reactant: COc1cccc(CBr)c1
Reactant: Oc1cccc2nc(Cl)ccc12
Product: COc1cccc(COc2cccc3nc(NCc4ccccc4OC)ccc23)c1

Procedure:
The title compound, MS: m/e=401.3 (M+H+), was prepared in accordance with the general method of example 63 from 5-hydroxy-2-chloroquinoline (CAS 124467-35-2), 2-methoxy benzyl amine and 3-methoxy benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CNO>C1COCC1>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:14])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Agent: CNO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 5 h
Yield: 77.6 %

Procedure:
5-amino-2,4-difluoro-benzoic acid (6 g, 34.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.3 g, 69.3 mmol) and 1-hydroxybenzotriazole (9.3 g, 69.3 mmol) was stirred in THF (100 ml). Diisopropylethylamine (7.2 ml, 41.5 mmol) and methylhydroxyamine hydrochloride (4.3 g, 51.9 mmol) were added thereto, and the solution was stirred for 5 hours. The resulting solution was extracted with ethylacetate and washed with salt solution. The resulting residue was recrystallized with diethylether to obtain the title compound 5 g (yield: 71%).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36].CN([CH:45]=[O:46])C>>[C:45]([OH:46])([C:29]([F:32])([F:31])[F:30])=[O:36].[F:32][C:29]([F:31])([F:30])[C:25]1[CH:24]=[C:23]([NH:22][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH2:9][N:8]([CH2:34][C:35]([OH:37])=[O:36])[CH2:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CBr
Product: O=C(O)C(F)(F)F
Product: O=C(O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (121.9 mg, 0.277 mmol) is dissolved in DMF (5 mL) and TEA (200 μl, 1.435 mmol) is added followed by t-butyl bromoacetate (101 μl, 0.693 mmol). The solution is stirred at rt overnight. The reaction is concentrated and then diluted with DCM (10 mL) and cooled to 0° C. TFA (5 mL) is then added and the ice bath is removed and the reaction is stirred at room temperature. The reaction is concentrated, basified with ammonium hydroxide, and diluted with ethyl acetate. The solution is then treated with 1N HCl. The ethyl acetate is removed, dried and concentrated to a residue. The residue is dissolved in DMSO and purified via HPLC (C18; 20-100% I/H2O with 0.1% TFA to obtain {4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl}-acetic acid. MS (ESI) m/z 498.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H) 8.32 (d, J=8.84 Hz, 1 H) 8.06 (s, 1 H) 7.88-7.95 (m, 2 H) 7.57 (t, J=7.96 Hz, 1 H) 7.40-7.45 (m, 2 H) 7.12 (dd, J=9.09, 2.02 Hz, 1 H) 6.74 (d, J=3.79 Hz, 1 H) 4.19 (d, J=9.35 Hz, 4 H), 3.43 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C)C=O>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 5.05 g, 0.0193 mol) in methylene chloride (100 mL) was added N,N-dimethylformamide (0.075 mL, 0.97 mmol) under an atmosphere of nitrogen. The reaction was cooled with ice/water, followed by slow addition of Oxalyl chloride (2.00 M of in methylene chloride, 10.8 mL, 21.6 mmol). The reaction mixture was stirred at room temperature for 3.0 hours. The reaction was cooled with ice/water, followed by addition of methanol (36.0 mL, 0.89 mol) slowly. The reaction was stirred at room temperature overnight. The reaction was concentrate and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a crude white solid 4.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]([OH:8])[CH2:6][C:5]([CH3:10])([CH3:9])[C:4](=[O:11])[C:3]=1[CH3:12].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.C(OC=C)C.[OH-].[Na+]>C(Cl)Cl>[CH3:13][CH:14]1[O:8][CH:7]2[CH2:6][C:5]([CH3:9])([CH3:10])[C:4](=[O:11])[C:3]([CH3:12])=[C:2]2[O:1]1
Reactant: CC1=C(O)C(O)CC(C)(C)C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=COCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=C2OC(C)OC2CC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
170 g (1.0 mol) of crystalline 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one were suspended in 500 ml of methylene chloride. First 500 mg (2.9 mol) of p-toluenesulfonic acid were added to the suspension and then 144 g (2.0 mol) of vinyl ethyl ether were run in at room temperature (RT) over the course of 2 hours (h). The mixture was then stirred at RT for 4 h and subsequently 100 ml of 5% strength sodium hydroxide solution were run in. The lower organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methylene chloride. The combined organic phases were washed with 200 ml of water and concentrated in a rotary evaporator. The residue was dried under greatly reduced pressure (oil pump) to give 2,4,6,6-tetramethyl-7,7a-dihydro-6H-benzo[1,3]dioxol-5-one as a yellow oil which was pure by thin-layer chromatography (TLC) and almost pure by gas chromatography (GC).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Product: CN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine (413 mg) obtained from 4-chloro-6-(4-methoxyphenyl)thieno[3,2-c]pyridine and N-methylpiperazine in the same manner as in Example 289-6 was dissolved in DMF (10 ml), followed by the addition of potassium carbonate (526 mg) and 2-bromoethanol (0.18 ml). The resulting mixture was stirred at 80° C. for 2 days, and then the resulting reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system), to give a yellow oil (202 mg, yield; 43%). The resulting oil was converted into a hydrochloride in a conventional manner, to give the title compound as yellow crystals.