Azzindani/Open_Reaction_Data huggingface dataset:
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.CC1(C)C(C)(C)OB([C:47]2[CH:51]=[CH:50][NH:49][N:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)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>[NH:48]1[CH:47]=[CH:51][C:50]([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]([CH3:37])([CH3:36])[CH3:38])[CH:3]=2)=[N:49]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 130 °C
Yield: 51.6 %

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 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.32 mmol), sodium carbonate (43 mg, 0.41 mmols) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.02 mmol) in 1.5 mL dimethylformamide under argon conditions. The mixture was heated at 130° C. overnight. The mixture was poured into water and was extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 39 mg (66% yield) of the title compound. Purity 100%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=1.C(OC([N:23]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:24]1)=O)(C)(C)C>>[CH2:8]([N:7]1[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=[C:3]1[CH2:2][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:25]1[CH:26]=[CH:27][NH:23][N:24]=1)[CH3:9]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ncc[nH]2)n1
Reactant: CCn1c(CCl)nc2cc(C#N)ccc21
Product: CCn1c(Cn2ccnc2-c2cc[nH]n2)nc2cc(C#N)ccc21

Procedure:
As described previously, nucleophilic displacement of 2-Chloromethyl-1-ethyl-1H-benzoimidazole-5-carbonitrile with 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester followed by usual work-up provides 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile; 1H NMR (CD3OD) δ 7.97 (s, 1H), 7.53 (brs, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=6.3 Hz, 2H), 6.79 (br s, 1H), 6.10 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H); m/z 318 [M+1].
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Li])CCC.Cl>C1COCC1.O>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([B:1]([OH:6])[OH:2])=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OCc2ccccc2)ccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 602.9 %

Procedure:
Triisopropyl borate (683 mg, 3.63 mmol) was added to a stirred solution of 4-(benzyloxy)-1-bromo-2-vinylbenzene (1.0 g, 0.346 mmol) in THF (9 mL). The solution was cooled in a CO2/acetone bath. A solution of n-butyllithium (1.45 mL of 2.5M in hexanes, 3.63 mmol) was added dropwise over 5 minutes. The cooling bath was left in place and was allowed to warm to room temperature. The mixture was treated with HCl (5 mL of 1N) and water (5 mL), stirred for 1 hour, and extracted with ethyl acetate (3×15 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to an oil which crystallized from diethyl ether/hexanes to provide colorless crystals of the desired product (530 mg, 57% yield). 1H NMR (300 MHz, CDCl3) δ 5.14 (s, 2H), 5.34 (d, J=12.44 Hz, 1H), 5.68 (d, J=17.57 Hz, 1H), 6.97 (dd, J=8.42, 2.56 Hz, 1H), 7.36 (m, 6H), 7.83 (dd, J=17.57, 10.98 Hz, 1H), 8.16 (d, J=8.42 Hz, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (0.070 g, 0.155 mmol) in THF (8 mL) was added 1M HCl (1.5 mL, 1.50 mmol). After stirring at ambient temperature for 2 hours, 1 M HCl (5 mL) was added and the reaction mixture stirred for an additional 16 hours. The mixture was neutralized with 1M NaOH and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 40 mg (77%) of desired product. MS APCI (+) m/z 337.3 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:32]2([C:43]3[CH:48]=[CH:47][C:46](F)=CC=3)[CH2:37][CH2:36][CH2:35][N:34](CC(O)=O)[C:33]2=O)=CC=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:33]1[C:32]2[C:37](=[CH:46][CH:47]=[CH:48][CH:43]=2)[CH2:36][CH2:35][N:34]1[C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]1=[O:17]
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (dt, J=4.4, 5.5, 4H), 7.22-7.11 (m, 3H), 7.06-6.94 (m, 5H), 4.75-4.53 (m, 2H), 4.27 (d, J=4.8, 2H), 3.82 (t, J=6.0, 1H), 3.65 (t, J=6.0, 1H), 3.52 (q, J=6.5, 2H), 2.91-2.67 (m, 4H); MS (DCI) m/z 447.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([NH2:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:26][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])([CH3:25])[CH3:24])=[N:7][CH:6]=2)[CH:13]=1
Reactant: Fc1ccc(Br)cc1-c1cnc(Br)nn1
Reactant: CC(C)(N)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(Nc1ncc(-c2cc(Br)ccc2F)nn1)c1ccccc1F
Yield: 67.6 %

Procedure:
3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine (2.8 g, 8.4 mmol), 2-(2-fluorophenyl)propan-2-amine (2.0 g, 12.6 mmol), K2CO3 (2.3 g, 16.8 mmol) and CH3CN (20 mL) was heated to 90° C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford a yellow solid (2.3 g), m/z=406.1 [M+H].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C(=O)N([I:50])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:50])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38B) (2.2 g, 3.53 mmol) in DCM (30 mL) was added NIS (0.795 g, 3.53 mmol). The mixture was stirred at r.t. overnight. The mixture was then diluted with EtOAc (300 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 2.6 g of the desired product. LC/MS (APCI): m/z 749.2 (M+H).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH:16][S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCOC(=O)Nc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCOC(=O)Nc1cccc2ccccc12

Procedure:
To a solution of 2-aminoethyl N-(1-naphthyl)carbamate [2.30 g(10.0 mmol.)] and triethylamine [1.53 ml(11.0 mmol.)] in chloroform(20 ml) was added, while stirring under ice-cooling, 2-chloroethanesulfonyl chloride [1.06 ml(10.0 mmol.)]. The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide, and dried, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel colum chromatography, eluting with hexane-ethyl acetate(1:1) to obtain the compound(270) [1.50 g(46.9%)] as a yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:11][CH2:12][N:13]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(S(C)(=O)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide, 65 μL triethylamine and 15 μL methanesulphonic acid chloride in 1 mL dichloromethane is stirred for three hours at ambient temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and the organic phase is evaporated down. The residue remaining is purified by RP-HPLC. Yield: 23 mg yellow solid (MH+=542; RT=3.07; Method A)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[CH:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Br)cs2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(-c3ccc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiophen-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.88) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.122 g, 0.55 mmol) according to the general procedure VI. Obtained as a white solid (0.115 g, 55%). MS (ISP) 412.2 [(M+H)+]; mp 175° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[N:19][C:18]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]2=3)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[N:19][C:18]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]2=3)[CH2:12][CH2:13]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1

Procedure:
tert-Butyl{1-[2-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 203, 0.213 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.15 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CS(C)=O.CCOC(C)=O>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:12]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2): A mixture of 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (360 mg, 2 mmol) and 4-aminomethyl-1-diphenylmethylpiperidine (420 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with AcOEt and washed twice with brine. The organic layer was dried over MgSO4 and evaporated, and then the residue was purified by column chromatography on silica gel to give 2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 520 mg (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[CH:4][C:5]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:12][C:11]=1[Cl:17]
Reactant: COC(=O)C(C)Br
Reactant: Cc1nn(-c2cc(Oc3ccc(O)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(Cl)cc2Cl)c(Cl)c1
Yield: 51.5 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 1.3 g (0.0029 mole) of 1-[2,4-dichloro-5-(2-chloro-4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one with 0.73 g (0.0044 mole) of methyl 2-bromopropionate and 0.60 g (0.0044 mole) of potassium carbonate in 60 ml of methyl ethyl ketone yielded 0.78 g of methyl 2-[4-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]-3-chlorophenoxy]propionate as an oil, compound 150 of Table 1.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].C1COCC1.[OH-].[Na+]>CO>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2ccccc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of [1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-indol-3-yl]-acetic acid methyl ester (440 mg, 1.0 mmol) in 1:1 THF:MeOH (20 ml) at room temperature, is added 1N NaOH aq (5 ml). The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is evaporated in vacuo, diluted with water (10 ml) and acidified to acidic pH with 6N HCl aq. The precipitated product is collected by filtration and recrystallised from 1:3 isopropyl alcohol:water. The product is dried under high vacuum at 50° C.; [M+H]+ 426.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])([OH:3])=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[Cl:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:10]([N:8]1[CH2:7][CH2:6][N:5]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[O:25])[CH:4]([C:1]([NH:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:3])[CH2:9]1)(=[O:12])=[O:11])[CH:22]=[CH:21]2
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Product: O=C(NCCN1CCOCC1)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1

Procedure:
In a similar manner to Example 4 except for the use of 4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide and 4-(2-aminoethyl)morpholine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:30][C:26]([NH:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:3]=1)([CH3:31])[C:27]([OH:29])=[O:28]
Reactant: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(NC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (398.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-methyl-2-[3-(1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-propionicacid (126.4 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 421.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Cl[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2)[CH:7]=1
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: Cc1ccnc(N)c1
Solvent: c1ccncc1
Product: Cc1ccnc(-n2sc3ccccc3c2=O)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
Using the method of Fischer and Hurni (Arzneimittel Forsch., 1964;14:1301) 5.4 g (0.05 mol) of 2-amino-4-methylpyridine in 50 mL of pyridine at 10° C. was reacted with 10.3 g (0.05 mol) of 2-chlorosulfanylbenzoyl chloride. The mixture was heated to 50° C. and maintained at that temperature for 2 hours. The mixture was cooled to 25° C. and filtered. The solid was recrystallized from benzene to give 4.5 g of the title compound, mp 195-196.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[I:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:31])([CH3:30])[CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:27]3[C:28]4[C:24](=[CH:23][CH:22]=[C:21]([I:20])[CH:29]=4)[C:25]([CH3:31])([CH3:30])[CH2:26]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (250 mg, 0.92 mmol), 6-iodo-3,3-dimethylindoline (250 mg, 0.92 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.22 mL, 0.92 mmol) in NMP (1.0 mL) and heating at 150° C. for 3 h in the microwave. After purification 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a foam. Mass Spectrum (ESI) m/e=510 (M+1).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH2:30](Br)[CH2:31][CH2:32][CH3:33]>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CCCCBr
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C3(c4ccc(O)cc4)CC3)cc2)C1
Product: CCCCOc1ccc(C2(C(=O)Nc3ccc(N4CCC(NCC(C)=O)C4)cc3)CC2)cc1

Procedure:
1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl -amino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60 (C27H35N3O3); MS(ESI): 450 (M+H+).