Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[O:79])[C@H:65]([CH2:68][CH2:69][CH2:70][NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[NH:66][CH3:67])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[C:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[O:79])[C@H:65]([CH2:68][CH2:69][CH2:70][NH:71][C:72]([O:74][C:75]([CH3:77])([CH3:76])[CH3:78])=[O:73])[N:66]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:67])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A cold solution (0° C.) of N-Boc-homophenylalanine (221 mg), diisopropylethylamine (228 μl), and anhydrous tetrahydrofuran (4 ml) was treated with PyBrop (398 mg), followed by the addition of a solution of Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (228 mg) in tetrahydrofuran (3 ml). The resulting solution was stirred for overnight. The precipitate was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated in vacuo and the product purified by silica gel chromatography (hexane/ethyl acetate) to give N-Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (260 mg): 1H NMR (400 MHz, CDCl3) δ1.43 (s, 18H), 1.7-2.0 (m, 8H), 2.58 (t, J=6.4 Hz, 2H), 2.6-2.85 (m, 5H), 3.0-3.4 (m, 4H), 4.4-4.5 (m, 1H), 4.9-5.0 (m, 1H), and 7.1-7.3 (m, 10H).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7]2.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH3:15][N:14]([CH2:13][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([CH:25]=[O:26])=[CH:12][CH:11]=2)[CH3:16]
Reactant: CN(C)C=O
Reactant: CN(C)Cc1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc2cc(C=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of potassium hydride (suspension in mineral oil, 0.79 g, 5.90 mmol) in anhydrous THF (60 mL) was added a solution of (5-bromo-1H-indole-2-ylmethyl)-dimethyl amine (1.24 g, 4.90 mmol) in anhydrous THF (20 mL) was added dropwise at 0° C. over a period of 15 minutes under nitrogen. Stirring was continued for 30 minutes at 0° C., then cooled to −10° C. n-Butyl lithium (1.6 M solution in hexanes, 7.4 mL, 11.7 mmol) was added rapidly. Stirring was continued at −10° C. for 1 h. Then, anhydrous DMF (5.0 mL) was added, and the mixture was allowed to warm to room temperature over 2 h. The reaction mixture was carefully quenched with 1N aq. HCl (10 mL). The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to give 2-dimethylaminomethyl-1H-indole-5-carbaldehyde as an orange-colored gummy material. Yield: 0.91 g (crude). This product was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C=Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 34.7 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250 g, 2.40 mmol, 1.2 eq), palladium(II) acetate (4.5 mg, 0.020 mmol, 0.01 eq), tri-o-tolylphosphine (12.2 mg, 0.04 mmol, 0.02 eq), and triethylamine (0.405 g, 4.0 mmol, 2.0 eq) in dimethylformamide (2 mL) was heated in a 120° C. oil bath for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a hexane/ethyl acetate gradient to provide the title compound as a yellow solid (166 mg, 35% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN1CCCC1=O>[CH2:12]([N:11]([C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCc1ccccc1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(Cc1ccccc1)c1cc(C#N)ccn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and N-methyl-N-benzylamine (1.0 ml, 7.8 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 2.5 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.47 g, 72%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[C:23]([Cl:35])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[CH:19][C:10]=3[O:9][CH2:8][CH2:7][NH:6][C:1](=[O:5])[CH2:2][OH:3])[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: O=C(O)CO
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: O=C(CO)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 3.71 (q, 2H), 3.78 (d, 2H), 4.36 (t, 2H), 5.28 (s, 2H), 5.49 (t, 1H), 7.13 (d, 1H), 7.21 (d, 1H), 7.32 (d, 1H), 7.35 (m, 1H), 7.56 (m, 2H), 7.71 (t, 1H), 7.87 (dt, 1H), 7.98 (d, 1H), 8.18 (t, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.82 (s, 1H); Mass Spectrum MH+ 480.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].CO[CH2:23][CH2:24]OC>O>[CH:23]([C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2)=[CH2:24]
Reactant: COCCOC
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1c(F)cnc2ccc(OC)nc12
Temperature: 85 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
To a solution of 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (2.0 g, 7.81 mmol), potassium carbonate (1.08 g, 7.81 mmol), tetrakis-triphenylphosphine (90 mg, 0.08 mmol) in DME (60 mL) and H2O (20 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (0.94 g, 3.91 mmol). After stirring for 10 h at 85° C. the reaction contents were concentrated and the product purified by chromatography (silica, 25% EtOAc in hexane) to give a low melting solid (1.43 g, 90%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (170 mg, 60%). MS (ISP) 570.2 [(M+H)+]; mp 132° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](F)=[C:24]([Cl:29])[CH:23]=2)[CH2:16]1)C1C=CC=CC=1.O>CCCC(C)C.CN(C)C=O.ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:7][CH2:6][CH:3]1[CH2:5][CH2:4]1)[CH2:21][C@H:17]1[O:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: OCC1CC1
Reactant: Fc1ccc(C[C@@H]2CN(Cc3ccccc3)CCO2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(C[C@@H]2CNCCO2)ccc1OCC1CC1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
Sodium hydride (50 mg, 1.25 mmol) was washed twice with isohexane and then suspended in anhydrous N,N-dimethyl formamide (0.5 mL), under an atmosphere of nitrogen and cooled to 0° C. Then cyclopropylmethanol (90 mg, 1.25 mmol) was added. When effervescence had finished intermediate (a), N-Benzyl-(R)-2-(3-chloro-4-fluorobenzyl)morpholine (0.10 g, 0.31 mmol) was added as a solution in N,N-dimethyl formamide (1.0 mL). The reaction was then warmed to 100° C. (bath temperature) for 6 hrs and cooled to room temperature. The mixture was poured into water (25 mL) and extracted with ethyl acetate (25 mL). The organic layer was washed with brine (10 mL×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to give a residue that was added to an SCX-2 column (10 g) as a solution in dichloromethane, washed with dichloromethane (6 mL×2) and methanol (6 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×6 mL). Combined ammonia washes were concentrated in vacuo to yield the desired product as colorless oil (85 mg). N-Benzyl-(R)-2-(4-cyclopropylmethoxy-3-chlorobenzyl)morpholine (82 mg, 0.22 mmol) was then dissolved in 1,2-dichloroethane (3 mL) and treated with 1-chloro-ethyl-chloroformate (94 mg, 0.66 mmol) and heated at 85° C. for 3 hrs. The reaction mixture was then concentrated in vacuo. The residue was dissolved in methanol (7 mL) and heated at 75° C. for 2.5 hrs. The reaction mixture was then concentrated in vacuo. The crude residue was dissolved in dichloromethane (1 mL) and the solution poured onto a SCX-2 column (2 g), eluting with dichloromethane (2 ml×2) and methanol (2 mL×2). The column was then washed with ammonia (2N in methanol, 2 mL×2). The ammonia washes were concentrated in vacuo. The crude residue was purified by preparative chiral HPLC to yield the desired morpholine example 27 as a yellow oil (10 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2OC)c(C)c1
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-methylbenzoate obtained in step 1 (3 g; 13.10 mmol), 2,4-dimethoxyphenylboronic acid (2.62 g; 14.4 mmol), potassium carbonate (9.05 g; 65.48 mmol), tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol) were taken in toluene (15 mL) and water (15 mL) under N2 atmosphere. The reaction mixture was purged with vacuum and degassed with N2 and then refluxed for 6 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil that was used without further purification (3.7 g, 98%). HPLC (Method A) Rt 4.74 min (Purity: 59.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])=[O:26])(=[O:21])[CH3:20]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cc1C

Procedure:
To a stirred solution of 4-chloro-2-methylaniline, 1-1, (10.0 g 0.071 moles) in toluene was added (24.7 mL 0.014 moles) of N,N-diisopropylethylamine, followed by slow addition of acetylsalicyloyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 9.4 grams of 1-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 88% pure, M+1 peak m/e 304.
Reaction SMILES: O1CCOCC1.Cl.O1[C:12]2([CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:46])=[C:22]([CH:45]=3)[C:23]([NH:25][C:26]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:36]=[CH:35][C:27]=3[C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH2:14][CH2:13]2)[O:11]CC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[OH:46][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]2)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[CH:35][C:27]=1[C:28]([OH:30])=[O:29])=[O:24]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCN(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
Dioxane (1.0 mL) and 6 mol/L hydrochloric acid (1.0 mL) were added to the obtained tert-butyl 2-(5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-hydroxybenzamido)-4-phenylbenzoate (0.070 g), followed by heating to reflux for 25 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto, followed by adjusting the pH to 5.2 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 0.026 g of 2-(2-hydroxy-5-(4-oxopiperidin-1-yl)benzamido)-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Cl)cc1Sc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of 1.28 g. (0.01 mol) of p-fluorothiophenol and 2.82 g. (0.01 mol) of 2-iodo-4-chlorobenzoic acid in 20 ml. of pyridine is added 1.3 g. (0.01 mol) of potassium carbonate, with stirring. Additional pyridine is added until solution is clear and then 0.3 g. of cuprous chloride is introduced. The resulting mixture is refluxed overnight, poured into ice-water, stirred and filtered. The aqueous solution is acidified and filtered. The solid is dissolved in 5% sodium bicarbonate solution and this solution is extracted with ether. The aqueous solution is acidified, extracted with ether and the washed, dried extract is concentrated to give 4-chloro-2-(4-fluorophenylthio)-benzoic acid, m.p. 204°-213° C. The latter (6.5 g., 0.023 mol) is heated for one hour with 105 g. of sulfuric acid to obtain 2-fluoro-6-chloro-9-thioxanthone, m.p 222°-224° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][CH3:50])=[C:44](B(O)O)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:49][CH3:50])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 66.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (5-fluoro-2-methoxyphenyl)boronic acid (55 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 55 mg (64% yield) of the title compound. Purity 92%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](OCC)=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH2:28])=O>C(O)CCC>[CH:1]1([N:6]2[C:10]3[C:11]4[N:12]([C:25]([C:21]5[S:20][CH:24]=[CH:23][CH:22]=5)=[N:27][N:28]=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC1=NCCc2c(CC)nn(C3CCCC3)c21
Reactant: NNC(=O)c1cccs1
Solvent: CCCCO
Product: CCc1nn(C2CCCC2)c2c1CCn1c(-c3cccs3)nnc1-2

Procedure:
A solution of 1cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine (3.739 kg, 14.3 moles) and 2thiophenecarboxylic hydrazide (2.237 kg, 15.8 moles) were heated in a solution in 1-butanol (37 L) to ˜90° C. in a 50 gal tank for 48 hours. At this point, some 1-butanol was distilled off to remove water azeotropically. The reaction was concentrated to a low volume and 4 gallons of methylene chloride (4 gal, 15 L) was added. The organics were washed twice with 1 N HCl (8 gal, 30.3 L) and concentrated by distillation to low volume. Isopropanol (16 L) was added to the concentrate and the resulting slurry was cooled and granulated. The product was collected by filtration and vacuum oven dried at 40° C. The yield was 3.25 kg (67%) of a white solid; mp 126° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:4]=[C:3]1[C:14]([NH2:17])([CH3:16])[CH3:15].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[C:3]([C:14]([N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]2=[O:23])([CH3:15])[CH3:16])=[N:4][N:5]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N1C(=O)c2ccccc2C1=O
Yield: 81.3 %

Procedure:
2-[4-Methyl-5-(2-chlorophenyl)-1,2,4-triazol-3-yl]propan-2-amine (1.19 g) and phthalic anhydride (704 mg) were diluted with acetic acid (5 ml), followed by stirring under heating and refluxing for 22 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was diluted with ethyl acetate (50 ml) and washed with a saturated aqueous sodium bicarbonate solution (30 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid was recrystallized from ethanol-water to obtain 1.47 g of 2-{1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-1-methylethyl}-1H-isoindole-1,3-(2H)-dione (white solid).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.C([O:21]C1C=CC(CO)=CC=1)C1C=CC=CC=1.CN1CCOCC1>ClCCl>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([OH:21])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
4-Nitrophenylchloroformate (260 g, 1.30 mmol) as a solution in 500 ml dichloromethane (DCM) is added to Wang resin (p-benzyloxybenzyl alcohol resin ex Calbiochem-Novabiochem, 350 g, 0.60 mmol) suspended in 1000 ml DCM and N-methylmorpholine (196 ml, 1.79 mmol) and stirred at room temperature for 18 hours. The resin is filtered and washed successively using methanol, DCM and ether to give WANG PARA-NITROPHENOL RESIN. [IR. 1761.5 cm−1; Loading 1.20 mmol/g].