Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][CH:35]([F:37])[F:36])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:38])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:44]>O1CCOCC1>[ClH:44].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][CH:35]([F:37])[F:36])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:38])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(OC(F)F)ccc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(OC(F)F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
230 mg of 6-tert-butyloxy-9-[5-(5-difluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (example 127) are dissolved in 1.4 ml of dioxane and combined with 1.434 ml of 4N HCl in dioxane. The reaction mixture is stirred for 16 hours at room temperature. The formed insoluble material is then collected by filtration, washed successively with 2×2 ml of dioxane and 2×2 ml of diisopropylether, and dried under vacuum to yield 107 mg of 9-[5-(5-difluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a brown powder. Yield=55%. Analytical LC/MS (method B): retention time=2.90 min., m/z=541.96 (positive ion mode).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C=CC=CC=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Brc1ccccc1
Product: Cc1ccc(Nc2ccccc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using Bromobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=308.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)CCBr
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)CCSc1ccc(Br)cc1

Procedure:
A mixture of 15 g (79 mmol) of 4-bromo-thiophenol (Compound 40), 3.16 g (79 mmol) of powdered sodium hydroxide and 150 ml of acetone was heated at reflux for 15 minutes. The refluxing mixture was then treated dropwise with a solution of 12 g (79 mmol) of 1-bromo-3-methylbutane (Compound 49) in 25 ml of acetone and then refluxed for a further 18 hours. The mixture was allowed to cool and the solvent removed in-vacuo. The residue was taken up in 25 ml of water and the mixture basified with 2N NaOH solution. The mixture was extracted with ether and the combined ether extracts washed successively with IN NaOH, water and saturated NaCl and then dried (MgSO4) The solvent was removed in-vacuo and the residue distilled (113-117 degrees C, 0.2 mm) to give the title compound as a colourless oil. PMR (CDCl3) & 0.93 (6H, d, J~6.6 Hz), 1.47- 1.58 (2H, m), 1.65-1.80 (1H, m), 2.90 (2H, t, J~7.8 Hz), 7.18 (2H, d, J~8.6 Hz), 7.39 (2H, d, J ~8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[CH2:48]([CH2:50][NH2:51])[OH:49]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:51][CH2:50][CH2:48][OH:49])=[O:23])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: NCCO
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Reaction time: 0.08 h

Procedure:
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, 0.88 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.29 g, 0.90 mmol) were added to methylene chloride (15 ml) and the mixture was stirred for 5 min. Ethanolamin (0.11 g, 1.8 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from diethyl ether gave 0.2 (59%) of the desired product.
Reaction SMILES: [C:1]1([CH:7]([CH2:13][CH:14]=[CH2:15])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]1([CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C(=O)OCC)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A solution of 6.0 g of ethyl 2-phenyl-4-pentenoate in 10 ml of tetrahydrofuran is added dropwise to a stirred suspension of 2.0 g of lithium aluminum hydride in 40 ml of tetrahydrofuran at room temperature. The resulting mixture is stirred at 40°-45° C. for 2 hours. Under ice-cooling, water (10 ml) is added dropwise to the reaction mixture in order to decompose the unreacted lithium aluminum hydride. The mixture is poured into 200 ml of ice-cold water and extracted with 200 ml of benzene. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluate to give 2.4 g of 2-phenyl-4-penten-1-ol as colorless oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[N:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)C=C.[CH:32]1([C:35]2[C:40]3[N:41]=[CH:42][S:43][C:39]=3[CH:38]=[CH:37][N:36]=2)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.[Cu]I>[Si:25]([O:24][C@H:21]1[CH:18]2[O:19][CH2:20][C@@H:16]([O:15][C:5]3[NH:4][C:12]4[C:7]([N:6]=3)=[N:8][C:9]([C:42]3[S:43][C:39]5[CH:38]=[CH:37][N:36]=[C:35]([CH:32]6[CH2:33][CH2:34]6)[C:40]=5[N:41]=3)=[C:10]([Cl:13])[CH:11]=4)[CH:17]2[O:23][CH2:22]1)([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:26])[CH3:27]
Reactant: c1cc2scnc2c(C2CC2)n1
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1COC2C1OC[C@H]2Oc1nc2nc(-c3nc4c(C5CC5)nccc4s3)c(Cl)cc2[nH]1
Temperature: 100 °C

Procedure:
Palladium tetrakistriphenylphosphine (200.0 mg, 0.173 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (500.0 mg, 0.865 mmol, Intermediate 5), 4-cyclopropylthiazolo[4,5-c]pyridine (183.0 mg, 1.038 mmol), cesium carbonate (1.409 g, 4.33 mmol), and copper (I) iodide (99.0 mg, 0.519 mmol) in degassed DMF (3.2 mL). The reaction mixture placed under nitrogen before being heated to 100° C. for 3 h. The reaction mixture was cooled to room temperature and added to EtOAc (80 ml). The mixture filtered and the solids washed with EtOAc (2×30 mL). The filtrate was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C27H32ClN5O4SSi 585.16 observed m/e: 586.17 (M+H)+ (Rt 1.18/1.8 min)
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:15])([CH3:14])[C:10](OC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>>[Si:1]([O:8][C:9]([CH3:15])([CH3:14])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(CO)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-(tert-butyldimethylsilyloxy)-2-methylpropanoate (1.00 g, 4.30 mmol) in hexanes (15 mL) at about −78° C. was added DIBAL-H (1.0 M in hexanes, 9.47 mL, 9.47 mmol) drop-wise over about 5 min. The solution was stirred at about −78° C. for about 5 min and the cooling bath was removed. The solution was warmed to ambient temperature and stirred for about 1 h. The reaction was then re-cooled to about 0° C. and was quenched with the slow addition of a saturated solution of sodium potassium tartrate (about 20 mL). The thick suspension was stirred at ambient temperature for about 2 h until the two layers were clear. The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give as the title compound (0.73 g, 83%) as a colorless oil: 1H NMR (CDCl3) δ 3.32 (s, 2H), 1.24 (s, 6H), 0.88 (d, J=2.9, 9H), 0.12 (d, J=3.2, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])(=[O:19])=[O:18])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:20]([CH3:27])([CH3:26])[C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Yield: 94.6 %

Procedure:
3.70g (9.10 mmol) of ethyl 2-[[3-(4-chlorophenyl)1,2-benzisoxazol-6-yl]sulfonyl]-2-methylpropionate was combined with 50 ml of methanol in a flask. The mixture was heated to reflux and an excess (50 ml) of 10% NaOH was added. Initially after the addition, the solution was clear yellow but after a few minutes a precipitate began to form. After refluxing for about one hour, the mixture was cooled and acidified with dilute HCl. The precipitate was collected and recrystallized from methanol to yield 3.27 g of 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]sulfonyl]-2-methylpropionic acid, m.p. 235°-239° C., with decomposition.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(OCCN2CCCCCC2)=NC=1.[N:39]1([CH2:46][CH2:47][O:48][C:49]2[N:54]=[CH:53][C:52]([NH:55][C:56]3[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=4)[CH2:65]3)=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:46][CH2:47][O:48][C:49]2[N:54]=[CH:53][C:52]([NH:55][C:56]3[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=3[CH:64]3[CH2:73][CH2:72][C:71]4[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=4[CH2:65]3)=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCCC3)nc1)C2
Agent: Brc1ccc(OCCN2CCCCCC2)nc1
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1Nc1ccc(OCCN3CCCCCC3)nc1)C2
Yield: 32.3 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[2-(5-bromopyridin-2-yloxy)ethyl]azepane according to an analogous synthetic method to Example 116, [6-(2-azepan-1-ylethoxy)pyridin-3-yl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (308 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (94 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][F:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH2:46][CH2:47][CH3:48]>C(OCC)(=O)C>[CH2:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][F:14])[CH2:54][CH2:53]1)=[O:51])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CF)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg (R)-2-tert-Butoxycarbonylamino-3-fluoro-propionic acid were added 0.18 ml N-ethylmorpholine, 237 mg TOTU and 115 mg 1-butoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 230 mg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[N:23](O)[C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])(O)=O.[Na+]>O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[NH:23][C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)n2O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
A 20% solution of TiCl3 in H2O was added dropwise at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)-phenyl]-acetate (355 mg, 0.844 mmol) obtained in Example 247.1 in MeOH (4.2 ml). The mixture was stirred for 3 h. at room temperature, subsequently poured into NaHCO3 solution/ice-water and extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2→CH2Cl2/MeOH 95:5). There were obtained 50 mg (15%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)-phenyl]-acetate as a yellowish solid; MS: 405 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH3:27])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]#[N:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([N:23]3[CH:32]([CH3:33])[CH2:31][C:30]4[C:25](=[CH:26][C:27](B5OC(C)(C)C(C)(C)O5)=[CH:28][CH:29]=4)[CH2:24]3)[N:20]=[C:19]([NH2:43])[N:18]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[NH2:43][C:19]1[N:20]=[C:21]([N:23]2[CH:32]([CH3:33])[CH2:31][C:30]3[C:25](=[CH:26][C:27]([C:2]4[CH:6]=[CH:5][N:4]([CH2:7][C:8]#[N:9])[N:3]=4)=[CH:28][CH:29]=3)[CH2:24]2)[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:18]=1
Reactant: N#CCn1ccc(Br)n1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3ccn(CC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (3-bromo-1H-pyrazol-1-yl)acetonitrile (14.4 mg, 0.0775 mmol), 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (18.0 mg, 0.0388 mmol), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (1.0 mg, 0.0014 mmol), and sodium carbonate (8.22 mg, 0.0775 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was vacuumed and refilled with N2 for 3 times and then stirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=444.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.C1COCC1.[CH:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.S(=O)(=O)(O)O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:16]=[CH:15][C:20]([Cl:21])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
0.5 mol of a 25% strength by weight 4-chlorophenylmagnesium chloride/THF solution is added dropwise in the course of 30 minutes to a boiling solution of 0.5 mol of 1,4-bromochlorobenzene and 0.25 g of Pd(dppf)Cl2 *CH2Cl2 in 100 ml of THF. After stirring under reflux for four hours, the mixture is hydrolyzed with dilute sulfuric acid (conversion 99%, selectivity 98%). The organic phase is freed from the solvent by distillation. The crude 4,4'-dichlorobiphenyl thus obtained is recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:19](=[O:20])[CH2:18][Cl:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred mixture of 4-fluorobenzylamine (685 uL, 6.0 mmol) and dry tetrahydrofuran (20 mL) was added triethylamine (1.25 mL, 9.0 mmol) under nitrogen. The resulting mixture was stirred for 10 minutes at ambient temperature. Next, chloroacetyl chloride (477 uL, 6.0 mmol) was added and the resulting mixture was stirred for 1 h. at ambient temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.09 g (91%) of the pure title compound.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:22][C:20]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(C)c([N+](=O)[O-])cn1
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of potassium ethoxide (0.262 g, 2.96 mmol) in diethyl ether (10 mL) and ethanol (1 mL) was added diethyl oxalate (0.404 mL, 2.96 mmol) in one portion and the resulting solution stirred for 10 min at rt. 2,4-Dimethyl-5-nitropyridine (Preparation 63, 0.400 g, 2.63 mmol) was added as a suspension in diethyl ether (1 mL)/ethanol (1.5 mL) and stirring continued for 16 h at rt. The mixture was filtered, washing with cold diethyl ether. The collected precipitate was dissolved in water and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and air dried. The solid was partitioned between ethyl acetate (150 mL) and water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a red solid which required no further purification. δH (CDCl3): 1.40 (3H, t), 4.40 (2H, q), 4.52 (2H, s), 7.11 (1H, s), 9.25 (1H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:6][CH:5]([OH:7])[C:4]1([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([S:30][CH3:31])[N:21]=1>C1COCC1.CN(C=O)C>[CH3:8][C:4]1([CH3:9])[C@H:3]([NH:2][C:24]2[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:20][N:21]=[C:22]([S:30][CH3:31])[N:23]=2)[CH2:6][C@@H:5]1[OH:7]
Reactant: CSc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CC1(C)C(N)CC1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask, 3-amino-2,2-dimethylcyclobutanol hydrochloride (peak 1, obtained above) (1.0 equiv.) and DIEA (1.3 equiv.) were combined in THF (1.0 M) and DMF (1.0 M). To this solution was added 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (1.0 equiv.) at 0° C. The mixture was allowed to warm to room temperature over 2 h; LCMS showed the desired product. Ethyl acetate was added and the organic phase was separated and dried over sodium sulfate. The organic phase was filtered and concentrated to a residue. The dried residue was purified by silica gel chromatography (Biotage column, 0-50% hexane in ethyl acetate; 340 g SNAP column). Concentration of the desired fractions afforded the title compound. The stereochemistry was determined as described for other intermediates described herein, by X-ray crystallography. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.22 (d, J=0.63 Hz, 1H) 5.21 (br. s., 1H) 4.08-4.23 (m, 1H) 3.78-3.91 (m, 1H) 2.80 (dt, J=11.66, 7.41 Hz, 1H) 2.52-2.57 (m, 3H) 1.79 (ddd, J=11.66, 9.46, 7.88 Hz, 1H) 1.67 (d, J=6.31 Hz, 1H) 1.24-1.32 (m, 3H) 0.97-1.06 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C1C=CC=CC=1>[CH:19]([NH:23][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: Cc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CCC(C)N
Solvent: c1ccccc1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(C)c1[N+](=O)[O-]

Procedure:
A nitration mixture, consisting of 16.1 ml. of H2SO4 (d 1.84) and 1.9 ml. of HNO3 (d 1.5), is heated to 55° C. and 3.5 grams of 5-chloro-2-(trifluoromethyl)toluene is slowly added. The mixture is heated for one hour at 55° C. followed by one hour at 110° C. The reaction mixture is cooled and poured onto ice to give 5-chloro-2-(trifluoromethyl)-4,5-dinitrotoluene as a cream-colored solid. The product is crystallized from cyclohexane to give 3.6 grams of cream-colored crystals, melting point 81° C. to 82° C. 1.8 Grams of 5-chloro-2-(trifluoromethyl)-4,6-dinitrotoluene is refluxed for 15 minutes with 3 ml. of mono-sec-butylamine and 30 ml. of benzene, cooled, filtered, washed with water until neutral, dried, and vacuum stripped to give 1.5 grams of N-sec-butyl-3-methyl-2,6-dinitro-4-(trifluoromethyl)aniline as a yellow solid, melting point 38° C. to 39° C.