Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:3]1([CH3:4])[CH:6]=[CH:7][C:8]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:9][CH:2]=1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
PdCl2/dppp (0.023 g, 1 mol %) is added and then o-bromobenzonitrile (0.72 g, 3.955 mmol) is added. The temperature rises from +10 to +300° C. over 15 min and then slowly falls to +250° C. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed using a 1N hydrochloric acid solution (15 ml). After extracting with ethyl ether, the organic phase is dried over potassium carbonate, filtered and then evaporated under vacuum. The oil thus formed is subsequently purified by chromatography (silica: 20 g; eluant: petroleum ether/ethyl acetate=95/5). The o-(p-tolyl)benzonitrile thus obtained is then harvested, with a yield of 96%, in the form of off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 470 mg (3.43 mmol) of 2-methoxybenzylamine to give 37 mg (28% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1C=CC(S(O)(=O)=[O:9])=[CH:6][CH:7]=1.O.[C:13]1(C)C=C[C:16](S(O)(=O)=[O:20])=[CH:15][CH:14]=1>>[CH2:7]1[CH2:6][O:20][CH2:1][CH2:2]1.[O:9]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C1CCOC1

Procedure:
TsOH*H2O 4-methylbenzenesulfonic acid hydrate, p-toluenesulfonic acid hydrate
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1.Cl>C(O)(=O)C.[Pt]>[ClH:1].[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCCCc1ccc(CCN)cc1
Agent: [Pt]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCCCC1CCC(CCN)CC1
Yield: 57 %

Procedure:
by hydrogenation of ethyl 5-[4-(2-aminoethyl)-phenyl]-pentanoate hydrochloride in the presence of platinum in glacial acetic acid. Yield 57% of theory; hydrochloride wax-like substance.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]([C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[C:23]([NH2:25])[N:24]=3)=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C>Cl.C(OCC)C>[NH2:25][C:23]1[N:24]=[C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH:10]3[CH2:9][NH:8][CH2:11]3)=[CH:18][CH:17]=2)[S:21][C:22]=1[C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Nc3nc(N)c(C(=O)c4cccc(F)c4)s3)cc2)C1
Agent: Cl
Solvent: CCOCC
Product: Nc1nc(Nc2ccc(OC3CNC3)cc2)sc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-[4-Amino-5-(3-fluoro-benzoyl)-thiazol-2-ylamino]-phenoxy]-azetidin-1-carboxylic acid tert-butyl ester (from Example 116, 160 mg, 0.33 mmol) was suspended in 1N HCl in diethyl ether and the mixture was stirred at room temperature overnight. The solid was filtered and passed through a C18 column eluting with aqueous ammonia in acetonitrile. The mixture was concentrated and the solid was filtered and dried to give a yellow solid. 110 mg, 87%. MS (ES) MH+=385.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Br:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[CH:11]=1
Reactant: CC(N=[N+]=[N-])c1cc(Br)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(1-azidoethyl)-4-bromopyridine (4.08 g, 16.54 mmol) in THF (100 mL) and water (10 mL) was added polymer-bound triphenylphosphine (200-400 mesh, -3 mmol/g loading; 10.97 g, 32.94 mmol). The suspension was then stirred at room temperature for 7 hours. The reaction was filtered over a coarse frit twice, then concentrated to afford the crude product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.32 (dd, J=5.2, 1.6 Hz, 1H), 4.13 (q, J=6.7 Hz, 1H), 1.83 (br s, 2H), 1.41 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: ClCc1ccncc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccncc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and pyridin-4-yl-methyl chloride. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6](=[O:13])[NH:7]2.FC1C=C2C(=C(F)C=1)NC(=O)C=N2.[H-].[Na+].CS(O[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:37]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1cnc2c(F)cc(F)cc2[nH]1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: O=c1cnc2cc(F)cc(F)c2[nH]1
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1

Procedure:
A mixture of 5,7-difluoroquinoxalin-2(1H)-one and 6,8-difluoroquinoxalin-2(1H)-one (Intermediate 195) (1.05 g, 5.77 mmol) was deprotonated with sodium hydride (0.31 g, 60% in oil, 7.75 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.8 mmol) as described for Intermediate 2. The residue obtained after aqueous workup was titurated in diethyl ether and filtered yielding 0.73 g of tert-butyl {1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193). The filtrate was concentrated and the residue was purified by chromatography on silica gel with 0-20% acetone in dichloromethane to yield 111 mg of tert-butyl {1-[2-(6,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 194).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][P:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])O.Cl(O)(=O)(=O)=O>C(OCC)C>[C:13]1([P:10]2(=[O:12])[C:8]3[CH:7]=[CH:6][CH:5]=[CH:2][C:3]=3[CH2:4][O:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=P(O)(Oc1ccccc1CBr)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: O=P1(c2ccccc2)OCc2ccccc21
Temperature: 26 °C
Yield: 75.3 %

Procedure:
A mixture of 2-bromomethylphenyl-phenylphosphonic acid (3.95 g, 0.0127 mole) and 10 ml. of 10% perchloric acid was heated at 100° C. for 4.5 hours with constant stirring. The reaction mixture was cooled to 26° C. and then extracted with methylene chloride. The methylene chloride layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to yield a yellow oil. This oil was distilled in a Kugelrohr at 180° C. and 0.6 torr to yield a colorless oil. The colorless oil was slurried in anhydrous diethyl ether, cooled during which period crystallization occured and then filtered to yield 1-phenyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (2.2 g, 76% yield) as white crystals having a melting point of 99°-101° C. and the following analysis:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1)(C)(C)C.Cl>>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Agent: Cl
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method K, {3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (I-39) was converted to the HCl salt of I-38 (30%): HRMS Calcd. for C23H21N5O3: 416.1720, Found 416.1722.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:32]([NH2:35])[CH2:33][CH3:34])[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:35][CH:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:33][CH3:34])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: CCC(N)C1CCC1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 72.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (73%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[C:21]([Cl:26])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:26][C:21]1[CH:22]=[C:23]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:16])[F:17])[N:24]=[C:19]([NH2:18])[N:20]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(-c2ccoc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.6 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethanol (100 mg, 0.4 mmol), 2-amino-4,6-dichloro-pyrimidine (60 mg, 0.36 mmol), cesium carbonate (468 mg, 1.44 mmol) ans 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 72%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:19](O)CCCC.IC1C(C2C3CCN(CC3)C2)=NN(COCC[Si](C)(C)C)C=1.CCO>CCO.C(OCC)(=O)C.C(N(CC)CC)C.CCO.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[C:7]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:19]
Reactant: CCCCCO
Reactant: CCCCOc1c[nH]nc1C1CN2CCC1CC2
Agent: C[Si](C)(C)CCOCn1cc(I)c(C2CN3CCC2CC3)n1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCOc1c[nH]nc1C1CN2CCC1CC2

Procedure:
Compound 52C was prepared following the procedure as described for the synthesis of compound 52A (see Scheme 10) using pentanol (25 ml) and 3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (50), (2 g, 4.61 mmol). Work-up and flash chromatography (gradient EtOH to EtOH/triethylamine 300/1) followed by a second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51C as an oil (0.46 g, 15%). LCMS (method B); Rt: 3.30 min, ([M+H]+=394).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:39])[NH:11][C:12]2[C:13]([CH3:38])=[C:14]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27]CC5C=CC=CC=5)=[CH:23][CH:22]=4)=[C:18]([C:35]#[N:36])[CH:17]=[N:16][N:15]3[CH:37]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CN(C=O)C>[N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:39])[NH:11][C:12]2[C:13]([CH3:38])=[C:14]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[C:18]([C:35]#[N:36])[CH:17]=[N:16][N:15]3[CH:37]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Cc1c(NC(=O)OCCN2CCOCC2)cn2ncc(C#N)c(Nc3ccc(OCc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)OCCN2CCOCC2)cn2ncc(C#N)c(Nc3ccc(O)cc3)c12
Yield: 92.8 %

Procedure:
[4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamic acid 2-morpholin-4-yl-ethyl ester 380C (0.79 mmol, 420 mg) and 10% Pd(C) (180 mg) in DMF (10 ml) were stirred under H2 gas (1 atm) for 24 hours. The reaction mixture was filtered to afford 380D as a yellow solid (320 mg, 92%). [M+H]+=437.21.
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>C(O)C>[N+:18]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nn1ccc2ccccc21
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-nitropyridine in ethanol at 70° C. for 3 hours in substantially the same manner as in Example 1. Recrystallized from ethanol, m.p. 170°-172° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[CH3:1][C:2](=[N:11][OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)=NO
Temperature: 25 °C
Reaction time: 120 h
Yield: 87 %

Procedure:
In a 50 ml round-bottom flask, a mixture of 2-octanone, hydroxylamine hydrochloride in pyridine was stirred, at room temperature under nitrogen blanket, for five days. The reaction mixture was then concentrated under vacuum to remove most of pyridine. The oil was then dissolved in dichloromethane. The product precipitated on standing. The product was obtained as a white solid in 87% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH3:15][N:16]1[CH:20]2[CH2:21][C:22]([CH2:24][CH:17]1[CH2:18][CH2:19]2)=[O:23].O>C(OCC)C>[OH:23][C:22]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:21][CH:20]2[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]2)[CH2:24]1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1C1(O)CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-bromoanisole (9.25 ml, 0.074 mol) in dry diethyl ether (110 ml) under argon was cooled to 0° C. and was treated with n-butyllithium (1.6M) (45.6 ml, 0.073 mol) slowly. The reaction mixture was then allowed to warm to room temp. After 0.5 h, a solution of tropinone (10.14 g, 0.073 mol) in dry diethyl ether (60 ml) was added causing the reaction mixture to reflux. Reflux was maintained for a further 0.5 h, before the reaction mixture was allowed to cool. Water (40 ml) was then added and the reaction mixture was stirred for 0.25 h. The organic layer was then separated, dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oily solid, which was triturated with petroleum ether (60-80). The resultant suspension was then filtered to give the title compound as a white solid, which was dried in vacuo (9.04 g, 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)[CH2:9][CH3:10]
Reactant: O=C1CNCCN1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2CCNC(=O)C2)ccc2c(C(F)(F)F)noc12

Procedure:
4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one was prepared as for Example 10 from piperazine-2-one and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: C(Cl)CCl.[NH:5]([C:7]1[C:8]2[N:9]([CH:17]=[CH:18][CH:19]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:6].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](O)=[O:30].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:17]1[N:9]2[C:10]3[C:15]([N:16]=[C:7]([NH:5][NH:6][C:29]([C:21]4[NH:20][C:28]5[C:23]([CH:22]=4)=[CH:24][CH:25]=[CH:26][CH:27]=5)=[O:30])[C:8]2=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: NNc1nc2ccccc2n2cccc12
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NNc1nc2ccccc2n2cccc12)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a stirred solution of EDC (94 mg, 0.49 mmol) and DMAP (cat.) in ethyl acetate (15 mL), compound 14a (77 mg, 0.39 mmol) and 2-indolecarboxylic acid (63 mg, 0.39 mmol) were added, portion wise, within 15 minutes. The resulting mixture was stirred at room temperature for 24 h, then shaken with sodium bicarbonate saturated solution and water. Evaporation of the dried extract gave a residue which was crystallized to give compound 6 as a white solid (82 mg, 62% yield); mp 186° C. (dichloromethane/light petroleum); IR (KBr) 3255, 1680 cm−1; 1H NMR (DMSO-d6) 6.75 (s, 1H), 7.05 (m, 1H), 7.20 (m, 4H), 7.40 (m, 3H), 7.65 (m, 1H), 8.10 (m, 1H), 8.35 (s, 1H), 9.55 (bs, 1H), 10.65 (bs, 1H), 11.80 (bs, 1 H). MS (CI) m/z 342 (MH+). Anal. Calcd. for C20H15N5O: C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27](Br)=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH3:30])[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][CH:8]=1)[CH3:2].[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:30])[N:23]=1)[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A suspension of (R)-3-(5-bromo-2-(N-cyclohexyl-N-methylamino)-pyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester (1.0 eq), 2-fluorophenylboronic acid (3.0 eq), K3PO4 (3.0 eq) and Pd(PPh3)4 (0.03 eq) in DMF under nitrogen was stirred at 90° C. for 5 h. The DMF was evaporated, the residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.5 M citric acid, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 6:4 hexanes/EtOAc to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:15]1([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of 4 g (17.2 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate and 5 g (54 mmol) of aniline in 40 ml of dioxan was stirred at room temperature for 24 hours. The mixture was then evaporated and 100 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 50 ml of aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The resulting solid was purified by crystallisation from aqueous ethanol to give 3.5 g (64%) of ethyl 4-phenylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Br:21][CH2:22][C:23](Br)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1])=[O:24]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)C1=O
Temperature: 0 °C

Procedure:
N-(2-Oxo-1-imidazolidinyl)carbamic acid, 1,1-dimethylethyl ester (12.0 g, 0.06 mmol) was dissolved in dichloromethane (75 ml) containing pyridine (5.2 g, 0.066 mol). The solution was cooled to 0° C. and treated slowly with bromoacetyl bromide (13.3 g, 0.066 mol). The solution was evaporated in vacuo to give a yellow oil. The oil was chromatographed on silica gel (~300 g) eluting with 10% ethyl acetate/dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid, 16.7 g.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>CC(O)=O.C(OCC)(=O)C>[C:1]([N:4]1[C:10]2[CH:11]=[C:12]([Br:16])[C:13]([OH:15])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCCc2cc(O)c(Br)cc21
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1-Acetyl-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine (D24, 2.81 g, 14 mmol) was stirred in glacial AcOH (50 ml) as N-bromosuccinimide (2.69 g, 15 mmol) was added portionwise over 20 min. The mixture was stirred for 30 min, diluted with ethyl acetate (500 ml), washed with water, K2CO3 solution and brine, dried (Na2SO4) and evaporated to give a tan solid, shown by NMR and TLC to be a mixture of dibromo and mono-bromo isomers. Chromatography on silica, eluting with 0-25% ethyl acetate/dichloromethane, yielded pure title compound (1.22 g, 31%) as a cream solid.