Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.01 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone described in Preparation Example R-4 (753 mg, 3.31 mmol) was dissolved in toluene (15 mL), and the solution was refluxed for 40 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added thereto, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (260 mg, 1.32 mmol, 44%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC[C@@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Crude 4-chloro-3-nitroquinoline (413.8 g, 1 eq.) was dissolved in dichloromethane (1.65 L). The solution was heated to reflux and then filtered through a layer of Celite® filter agent. The filtrate was cooled to 5° C. with stirring. Triethylamine (305.4 mL, 1.1 eq.) was added in a single portion. The reaction mixture was stirred for 15 minutes. (R)-(−)-2-Amino-1-butanol (205 mL, 1.1 eq.) was added dropwise while maintaining the temperature of the reaction mixture below 40° C. The reaction mixture was allowed to stir at ambient temperature for several days. The reaction mixture was cooled to −30° C. A yellow precipitate was isolated by filtration, washed with very cold dichloromethane and then sucked dry. The solid was slurried for 1 hour with cold 80/20 water/methanol (1 L), isolated by filtration, washed with cool water, washed with very cold methanol (2×300 mL), and then sucked dry on the filter overnight to provide 475 g of (2R)-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].Cl>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Product: Clc1cccc(Nc2ncnc3[nH]ccc23)c1

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4chloro-7H-pyrrolo[2,3-d]pyrimidine and 3-chloroaniline (3.4%). LC-MS: 245 (MH+); anal. RP18-HPLC RT: 3.74 min; HCl salt MP: 227-228° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)[CH2:2][CH2:3][CH3:4].Br>O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(=O)O)c(=O)c2ccc(OC)cc21
Agent: Br
Solvent: O
Product: CCCCn1cc(C(=O)O)c(=O)c2ccc(O)cc21

Procedure:
5.0 g. (18 mmol) of 1-butyl-1,4-dihydro-7-methoxy-4-quinolone-3-carboxylic acid is refluxed for 4 hours in 65 ml. of hydrobromid acid (48%). The mixture is then poured into water; the solid product is filtered off and recrystallized from dimethylformamide.
Reaction SMILES: ClC1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[N:43]1([C:41]2[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]([C:59]3[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=3)=[C:37]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=3)[N:42]=2)[CH2:44][CH2:45][CH2:46]1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CCC3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.423 min, [M+H]30 =440.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]=[O:15])=[CH:5][N:6]2[CH:11]([CH3:13])[CH3:12].[F:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[CH3:12][CH:11]([N:6]1[C:7]2[C:3](=[C:2]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[C:21]=3[F:24])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:14]=[O:15])=[CH:5]1)[CH3:13]
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: CC(C)n1cc(C=O)c2c(Br)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(C=O)c2c(-c3ccc(F)c(F)c3F)cccc21
Temperature: 140 °C
Yield: 68.7 %

Procedure:
To a solution of 4-bromo-1-(propan-2-yl)-1H-indole-3-carboxaldehyde (100 mg, 0.376 mmol) and 2,3,4-trifluorophenylboronic acid (79 mg, 0.451 mmol) in dioxane (2 mL) and water (0.5 mL) in a 5 mL microwave reaction vial was added potassium carbonate (156 mg, 1.13 mmol) and dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium (II) (25 mg, 0.038 mmol). The reaction was placed under nitrogen, sealed and heated in a microwave reactor at 140° C. for 15 minutes. The solvent was removed in vacuo and the residue was partitioned with ethyl acetate and aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (COMBI FLASH 24 gm column, gradient of 0-100% ethyl acetate/hexanes) to give the title intermediate (82 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH:7]([CH3:10])[CH:8]=[CH2:9].C(=O)([O-])[OH:13].[Na+]>CC(C)=O.O>[OH:1][CH:5]1[CH:4]=[CH:3][C:2](=[O:13])[CH:6]1[CH:7]([CH3:10])[CH:8]=[CH2:9]
Reactant: C=CC(C)C(O)c1ccco1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CC(C)C1C(=O)C=CC1O
Reaction time: 48 h
Yield: 61 %

Procedure:
1-(2-Furyl)-2-methyl-3-buten-1-ol (122 g, 0.8 mole) was dissolved in a 2:1 mixture (1.2 liter) of acetone and water in a reactor, and polyphosphoric acid (20 g) was then added. Thereafter, reaction was carried out at 50° to 60° C. for about 48 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (200 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 74 g (yield, 61%) of pure (±)-3-hydroxy-2-(1-methyl-2-propenyl)-4-cyclopenten-1-one having a boiling point of 122°-130° C./3 mmHg.
Reaction SMILES: Br[C:2]1[C:3]([CH2:9]Br)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[CH2:9][N:14]([C:11](=[O:13])[CH3:12])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=[CH:18][C:2]=2[CH:7]=1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: BrCc1ncc(Br)cc1Br
Product: CC(=O)N1Cc2ncc(Br)cc2C=Cc2ccccc21
Yield: 16 %

Procedure:
Compound 52C (46.6 mg, 16%) was prepared from bb (147 mg, 0.91 mmol) and 52B (300 mg, 0.91 mmol) in two steps by a route analogous to that used for the preparation of 1D.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[CH:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>CC(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:21])[N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1c(C)nc2c(Cl)cc(C(F)(F)F)cn12
Temperature: 150 °C
Yield: 17.3 %

Procedure:
A mixture of 3-chloro-5-(trifluoromethyl)pyridin-2-amine (2 g), ethyl 2-chloro-3-oxobutanoate (1.18 g) and 2-propanol (12 mL) was stirred with heating with microwave irradiation at 150° C. for 7 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][C:22]([CH:14]([C:13]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])([OH:21])[CH2:23][CH2:24]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCC(=O)O
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a solution of 15 mL (124 mmol) diisopropyl amine in 90 mL anhydrous THF at −40° C. was added dropwise 45 mL (113 mmol) of n-butyl lithium (2.5 M in hexanes) The reaction mixture was warmed to 0° C. A solution of 6.7 mL (62.1 mmol) hexanoic acid acid in 60 mL anhydrous THF was added dropwise. The reaction mixture stirred at −20° C. for an additional 20 m. The reaction mixture was cooled to −78° C. A solution of 15 g (64.3 mmol) benzyl 4-oxo-1-piperidine-carboxylate in 60 mL anhydrous THF was added dropwise. The reaction mixture slowly warmed to room temperature over 18 h. The reaction was quenched by addition of 25 mL of water. The mixture was acidified to pH 2 with 6N HCl. The aqueous layer was thrice extracted with EtOAc. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. Toluene was added to the light, yellow oil and evaporated under reduced pressure to provide 21.5 g (99%) of 4-(1-carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester: ms [M]+=350.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH2:19]1)[CH3:17]>O>[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][C:23]([CH:14]=[O:15])=[CH:24][C:20]=2[CH2:19]1)[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CCC1Cc2ccsc2C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCC1Cc2cc(C=O)sc2C1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
115 cm3 of phosphorus oxychloride and 155 cm3 of N-methylformanilide are stirred for 30 minutes at ambient temperature. 228 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene, prepared as in Example 5, are added dropwise to this complex whilst the temperature is maintained at 30° C., if necessary by cooling with iced water. After the end of the addition, the reaction mixture is stirred for a further 6 hours at ambient temperature and is then poured carefully on to a mixture of water and ice. The organic products are extracted with ether. The extract is washed with water until neutral and then dried over sodium sulphate. The ether is evaporated and the residue obtained (290 g) is distilled in vacuo. This gives 205 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene-2-carboxaldehyde as a liquid, b.p. 112°-115° C./0.6 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14](C=O)=[C:13]([B:19]2[O:23][C:22](C)(C)C(C)(C)[O:20]2)[CH:12]=1)[C:5]#[N:6].[BH4-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]2[CH2:22][O:23][B:19]([OH:20])[C:13]=2[CH:12]=1)[C:5]#[N:6]
Reactant: CC1(C)OB(c2cc(Oc3ccc(C#N)cc3F)ccc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of 3-fluoro-4-[4-formyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-benzonitrile (4) (8.23 g, 22.4 mmol) in MeOH (anhydrous, 150 mL) was added NaBH4 (2.56 g, 67.2 mmol) slowly. The reaction was stirred at room temperature for 2 hours, then 1 M HCl (50 mL) was slowly added. The reaction was stirred over night. The methanol was evaporated under vacuum. Much of white solid was formed during the evaporation. The solid was filtered, washed with water, and air-dried to afford 3-fluoro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (5) 4.5 g in 75% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.06 (dd, J=10.94, 1.95 Hz, 1 H), 7.67 (d, J=8.60 Hz, 1 H), 7.49 (d, J=8.21 Hz, 1 H), 7.36 (d, J=2.34 Hz, 1 H), 7.29 (dd, J=8.21, 2.34 Hz, 1 H), 7.13 (t, J=8.40 Hz, 1 H), 4.98 (s, 2 H). ESMS (m/z): 268 (M−H)−. HPLC: 95.27% (220 nm), 97.09% (254 nm), 97.20% (maxplot).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1
Product: Nc1cc2ncnc(Nc3ccccc3)c2cn1
Temperature: 180 °C
Yield: 50.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.136 g, 0.7 mmol) and aniline (0.5 mL, 5.5 mmol) is refluxed under N2 at 180° C. for 2 h. The reaction mixture is cooled to 25° C., when it precipitates. The solid is collected by suction filtration and recrystallized from isopropanol, and dried in a vacuum oven overnight. 7-Amino-4-anilinopyrido[4,3-d]pyrimidine (84 mg, 51%) is isolated as a light yellow solid. 1H NMR (DMSO) δ 9.82 (1H, s), 9.34 (1H, s), 8.37 (1H, s), 7.80 (2H, d, J=7.5 Hz), 7.38 (2H, t, J=7.5 Hz), 7.12 (1H, t, J=7.5 Hz), 6.61 (2H, brs) 6.43 (1H, s).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[N:55]1([CH2:60][CH2:61][O:62]C2C=CC(O)=CC=2)[CH2:59][CH2:58][CH2:57][CH2:56]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([O:62][CH2:61][CH2:60][N:55]4[CH2:59][CH2:58][CH2:57][CH2:56]4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: Oc1ccc(OCCN2CCCC2)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(OCCN4CCCC4)cc3)s1)CC2

Procedure:
The title compound 114 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 106B: 1H NMR (DMSO-d6): δ 12.90 (s, 1H), 9.75 (s, 1H), 8.04 (d, J=7.93 Hz, 1H), 7.80 (d, J=7.93 Hz, 1H), 7.68 (d, J=7.32 Hz, 2H), 7.35-7.50 (m, 4H), 6.86-6.93 (m, 4H), 4.83 (s, 2H), 4.19-4.21 (m, 2H), 3.92 (d, J=6.26 Hz, 2H), 3.72 (d, J=5.95 Hz, 1H), 3.55 (br, 4H), 3.10-3.18 (m, 4H), 3.03 (t, J=5.8 Hz, 2H), 1.85-2.02 (m, 6H). ESI (+)/MS: 684 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:12]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC.CSC>C(Cl)(Cl)Cl>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[C:15]([Br:17])[CH:14]=1
Reactant: O=C(Nc1cc(Br)cc(-c2nc3ccccc3o2)c1)OCc1ccccc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To a solution of (3-benzoxazol-2-yl-5-bromo-phenyl)-carbamic acid benzyl ester (0.160 g, 0.38 mmol) in chloroform (5.0 mL) at room temperature was added BF3-Et2O (0.21 g, 1.5 mmol) and dimethylsulfide (0.24 g, 3.78 mmol). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed and residue was purified by preparative TLC eluting with 3:1/hexanes:ethyl acetate to give 3-benzoxazol-2-yl-5-bromo-phenylamine (0.10 g, 92%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(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)C=CC=CC=1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[N:3]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(NC2CCCC2)n1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(COc2ccc(-c3ccnc(NC4CCCC4)n3)cc2)cc1
Yield: 61.3 %

Procedure:
(4-chloro-pyrimidin-2-yl)-cyclopentyl-amine (100 mg, 0.51 mmol) was reacted with (4-benzyloxyphenyl)boronic acid (173 mg, 0.76 mmol), tetrakis(triphenylphosphino)palladium (44 mg, 0.04 mmol), and aq. 2 N sodium carbonate (1.01 mmol, 0.51 mL) as described in general procedure Q, method Q1, to give 108 mg (62%) of [4-(4-benzyloxy-phenyl)-pyrimidin-2-yl]cyclopentyl-amine. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate, 4:1 then 1:1. LCMS m/z: 346 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH:16]=[N+:17]([CH3:19])[CH3:18].BrC1C=C(C=CC=1)C=O.CNC>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]([CH3:19])[CH3:18])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1cccc(Br)c1
Agent: CNC
Agent: O=Cc1cccc(Br)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Br)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (3-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].[Si:5]([O:12][C@H:13]1[CH2:17][N:16]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@H:15]([C:31](OC)=[O:32])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO>[Si:5]([O:12][C@H:13]1[CH2:17][N:16]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C@H:15]([CH2:31][OH:32])[CH2:14]1)([C:8]([CH3:11])([CH3:9])[CH3:10])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h
Yield: 53 %

Procedure:
Lithium chloride (1.21 g, 28.49 mmol) and sodium borohydride (1.08 g, 28.49 mmol) were added to a solution of (4) in (4.44 g, 9.49 mmol) in methanol (50 ml) at RT. The reaction was stirred overnight and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 0.1M aqueous HCl, sat. sodium bicarbonate solution and brine. The organic layers were dried with sodium sulfate and concentrated in vacuo. The resulting crude product was purified via column chromatography using ethyl acetate/hexane gradients to yield ((2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-yl)methanol (5) (2.23 g, 53%) as a white solid. MS m/z 440.2 (M+H)+; retention time=3.006 min, method [1].
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[N:6]=1.[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([CH3:24])[NH:20][C:19]=1[C:25]([NH:27][C@@H:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[O:34][CH2:35][CH:36]=[CH2:37])=[O:26].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([CH3:24])[NH:20][C:19]=1[C:25]([NH:27][C@@H:28]1[CH2:33][CH2:32][N:31]([C:2]2[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]3[N:11]([CH3:12])[N:10]=[CH:9][N:8]=3)[N:6]=2)[CH2:30][C@@H:29]1[O:34][CH2:35][CH:36]=[CH2:37])=[O:26]
Reactant: C=CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Reactant: COC(=O)c1sc(Cl)nc1-c1ncnn1C
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
Methyl 2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Intermediate 2, 77.91 mg, 3.02 mmol) was added to a solution of 3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 20, 100 mg, 3.02 mmol) and N,N-diisopropylethylamine (0.362 mL, 0.06 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and the resulting reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and poured into water (20 mL). The solid that formed was collected by filtration, washed with diethylether (25 mL) and dried to afford Methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (90 mg, 70%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16]C(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:38]=[N:37][CH:36]=2)[C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][C:5]=1[NH2:16]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(-c2cnco2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 28.5 %

Procedure:
2-Acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (880 mg, 3.043 mmol) in MeOH (10 mL) was treated with potassium carbonate (463 mg, 3.35 mmol) and toluene-4-sulfonyl methylisocyanide (594 mg, 3.04 mmol) and the mixture was refluxed for 5 h. The reaction mixture was cooled to r.t., concentrated in vacuo and the residue was purified by flash chromatography (100 g silica gel, DCM) to give the title product (248 mg, 28%) as a yellow powder. API-ES: m/z 287.1 [M+H]+, rt 4.40 min.