Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31]CC)=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:41][O:40][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:25]=1[NH:24][C:16]1[N:15]=[C:14]([NH:13][C:5]2[CH:4]=[CH:3][C:2]([N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[C:10]3[C:6]=2[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]3)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=1)[CH2:29][P:30](=[O:37])([OH:31])[O:34][CH2:35][CH3:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 1.2 %

Procedure:
A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate (200.0 mg, 0.3038 mmol), 1-methylpiperazine (202 uL, 1.82 mmol), bis(dibenzylideneacetone)palladium(0) (34.9 mg, 0.0608 mmol), Cs2CO3 (297 mg, 0.911 mmol) in 1,4-dioxane (20 mL) was evacuated and purged with nitrogen three times and allowed to stir at 100° C. overnight. The reaction mixture was passed through a Thiol-SPE cartridge to remove Pd and the crude material was purified by MDP. The resulting material, diethyl (3-methoxy-4-{[4-{[2-methyl-7-(4-methylpiperazin-1-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl) phosphonate, was taken up in conc. HCl (2.0 mL) and heated at 80° C. for 2 hours. The crude material was again purified by MDP to obtain the title compound (2.3 mg, 1.2% yield). 1H NMR (400 MHz, methanol-d4) δ=1.26 (t, J=6.9 Hz, 3 H), 2.99 (s, 3 H), 3.17 (s, 3 H), 3.18 (d, J=20.7 Hz, 2 H), 3.24-3.29 (m, 2 H), 3.33-3.36 (m, 2 H), 3.38-3.46 (m, 2 H), 3.58 (br. s., 2H), 3.88 (s, 3 H), 4.03 (quin, J=7.1 Hz, 2 H), 4.48 (s, 2 H), 7.00 (d, J=8.1 Hz, 1 H), 7.10 (s, 1H), 7.21 (d, J=8.8 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1 H), 8.32 (s, 1 H), 8.39 (br. s., 1 H). MS (ES+): m/z 650.29 (100) [MH+]; HPLC: tR=0.63 min (UPLC, purity).
Reaction SMILES: BrC1C=NC(I)=NC=1.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC.C(=O)([O-])[O-].[Na+].[Na+].F[C:34]1[C:39](F)=[C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:37]=[CH:36][C:35]=1[C:50]1[N:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1>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.COCCOC>[CH2:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([C:50]2[N:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=2)=[CH:34][CH:39]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1cnc(I)nc1
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cc1
Yield: 43 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine (2 (1.23 g, 4.32 mmol), 4-octyloxyphenylboronic acid 7 (1.33 g, 5.18 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.13 mmol), DME (30 ml), aqueous 2M sodium carbonate (30 ml). The experimental procedure was as described for compound 4 to yield the phenylpyrimidine 8 (0.67 g, 43%) (from EtOH), m.p. 95.0° C.; νmax /cm-1 (KBr) 2920, 1605, 1525, 1425, 1260, 1170, 1120 and 790; δ0.90 (3H, t, Me), 1.20-1.55 (10H, m), 1.84 (2H, quint, OCH2CH2), 4.02 (2H, t, OCH2), 6.97 (2H, d, J 7,3'- and 5'-H), 8.33 (2H, d, J 7,2'- and 6'-H) and 8.76 (2H, s, 4- and 6-H); m/z 366 (M+), 364 (M+), 252 (M+ -C8H16), 250 (M+ -C8H16), 195 and 186.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2.P([O-])(O)(O)=[O:18].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([OH:18])=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: O=P([O-])(O)O
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(cc1C(=O)O)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a mixture of 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (2.0 g) synthesized by a known method (WO2001/077100), sodium dihydrogen phosphate (1.63 g) and 2-methyl-2-butene (4.3 ml) in tert-butanol (52 mL) and water (8 mL) was slowly added sodium chlorite (2.89 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. After cooling to 0° C., the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, and washed with hexane to give 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (0.72 g, 34%) as white crystals.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulphonyl)benzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11]([OH:13])=O)([O-:7])=[O:6].C(#N)C.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 76 %

Procedure:
After adding 68.6 g of thionyl chloride to a mixture of 105.7 g of 3-nitro-4-chlorobenzoic acid and 800 ml of acetonitrile, the resultant mixture was refluxed for 4 hours. After cooling the reaction mixture, the solvent was distilled off and the residue formed was dissolved in chloroform. To the solution formed was added 63.5 g of triethylamine and after adjusting the temperature thereof to 5° C., a chloroform solution of 148.6 g of N-methyloctadecylamine was added dropwise to the solution. After the reaction was over, water was added to the reaction mixture and the organic phase thus formed was recovered and dried over anhydrous sodium sulfate. After removing inorganic matters by filtration from the organic phase, the solvent was distilled from the organic phase and the residue was recrystallized from a 1:3 mixture of acetonitrile and methanol to provide 186 g of the above-described compound with a yield of 76.0%. The melting point thereof was 55° C. to 56° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]([C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=O.Cl.[O:37]1C[CH2:40][CH2:39][CH2:38]1>>[OH:37][CH2:38][CH2:39][CH:40]=[CH:9][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: O=C(c1ccc(C=CCCO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Hydroxypropyltriphenylphosphonium bromide (2.4 g) is dispersed into tetrahydrofuran (50 ml) and thereto is added dropwise lithium diisopropylamide (a solution in 1.99N tetrahydrofuran) (6.1 ml) at 0°-5° C. After adding, the mixture is stirred at 0°-5° C. for 1 hour and thereto is added 1-[1-(4-formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2 g). The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water and adjusted to pH 4-5 by adding conc. hydrochloric acid. The mixture is extracted with ethyl acetate and dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1→ethyl acetate:methanol=20:1) to give 1-{1-[4-(4-hydroxy-1-butenyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[S:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH2:10]1.BrC(C)C.O>O1CCCC1>[CH:1]([CH:10]1[C:11](=[O:15])[NH:12][CH:13]=[CH:14][S:9]1)([CH3:3])[CH3:2]
Reactant: O=C1CSC=CN1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)Br
Product: CC(C)C1SC=CNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropylamide (10.4 mmol) in tetrahydrofuran (5 ml) is cooled to −78° C. under a nitrogen atmosphere, and a solution of 3,4-dihydro-2H-1,4-thiazin-3-one (500 mg, Reference compound No. 39-1) in tetrahydrofuran (5 ml) is added dropwise thereto. Then, 2-bromopropane (640 mg) is added dropwise thereto, and the mixture is stirred for three hours. The temperature is raised to room temperature, and the mixture is stirred for two days. Water is added to the reaction mixture under ice cooling, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 45.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.032 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.CCOCC>C1(C)C=CC=CC=1.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:30]=[CH:31][O:27][CH:28]=1
Reactant: OB(O)c1ccoc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.447 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of furan-3-boronic acid (0.23 g) in ethanol (1 ml). The mixture was heated under reflux for 5.5 hours, cooled and then poured into ether (25 ml) and water (25 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (25 ml). The combined organic layers were washed with water (2×25 ml), brine (25 ml) and then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (30 g) eluted with dichloromethane. After combination and evaporation of suitable fractions the residue was further purified by HPLC. Combination and processing of suitable fractions gave the title compound as a white solid, m.p. 180-1° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:17]([Cl:18])=[CH:16][S:15][CH:14]=1)=S.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C>C1COCC1.O>[Cl:18][C:17]1[C:13]([NH:12][C:10]2[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:14][S:15][CH:16]=1
Reactant: Nc1cc(F)ccc1NC(=S)Nc1cscc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]c(Nc3cscc3Cl)nc2c1
Yield: 24.3 %

Procedure:
1-(2-Amino-4-fluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (625 mg) was dissolved in THF and a solution of NaOH (0.207 g) in water (9 ml) was added. Within 5 min a solution of p-toluenesulfonyl chloride (0.395 g) in THF (10 ml) was added dropwise. After stirring for one hour at room temperature water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4), treated with charcoal, filtered and the solvent evaporated to yield the desired product (135 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:23]([O:25][CH3:26])=[O:24])=[N:4][C:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:52]([O:56][CH3:57])(=[O:55])[CH:53]=[CH2:54]>CN(C)C=O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[N:4]=[C:3]([C:23]([O:25][CH3:26])=[O:24])[C:2](/[CH:54]=[CH:53]/[C:52]([O:56][CH3:57])=[O:55])=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1C(=O)OC
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A suspension of methyl 3-bromo-6-(dibenzylamino)pyridine-2-carboxylate (3.16 g, 7.68 mmol), palladium acetate (172 mg, 0.768 mmol), triphenylphosphine (404 mg, 1.54 mmol), potassium carbonate-(1.59 g, 11.5 mmol) and methyl acrylate (1.21 mL, 15.4 mmol) in N,N-dimethylformamide (77 mL) was stirred with heating at 120° C. for 12 hr. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (2.60 g, yield 81%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CCN(C(C)C)C(C)C>C(#N)C.CCOC(C)=O.O>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Yield: 63.7 %

Procedure:
A solution of 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Example 31) (179 mg, 0.424 mmol), ethyl 4-bromobutanoate (0.061 ml, 0.424 mmol) and DIPEA (0.074 ml, 0.424 mmol) in Acetonitrile (5 ml) was heated at 70° C. overnight. Additional ethyl 4-bromobutanoate (0.061 ml, 0.424 mmol) and DIPEA (0.074 ml, 0.424 mmol) were added and the reaction heated for a further 5 hrs. The cooled reaction was diluted with EtOAc/water, separated, the organics dried over magnesium sulphate and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:2 to give the title compound (135 mg) as a colourless oil. MS (ES): C26H3035ClN3O5 requires 499; found 500 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:12]Br.C(OCC)C>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrBr
Reactant: COc1ccc(C#N)c(N)c1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(N)c(C#N)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Amino-4-methoxybenzonitrile (4.47 g, 30.2 mmol) is dissolved in 70 ml of dioxane and treated at 0° C. with bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at 0° C. for one hour. After addition of diethyl ether, the resulting crystals are filtered off with suction. The desired product is obtained in 81% yield (5.52 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1.Br[CH2:33][C:34]([NH2:36])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:33][C:34]([NH2:36])=[O:35])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1
Reactant: NC(=O)CBr
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Yield: 87.7 %

Procedure:
A solution of Example 28H (0.100 g, 0.227 mmol), 2-bromoacetamide (0.124 g, 0.681 mmol), cesium carbonate (0.390 g, 1.14 mmol), and tetrabutylammonium iodide (0.011 g, 0.024 mmol) in dimethylformamide (2.5 mL) was stirred at 25° C. for 72 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the free acid (0.099 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](=[N:27][OH:28])[C:9]2[C:10](F)=[C:11]([F:25])[C:12]([N:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)=[C:13]([CH2:15][OH:16])[CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:8]2[C:9]3[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([N:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)=[C:11]([F:25])[C:10]=3[O:28][N:27]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[C@@H]1CN(c2c(CO)cc(C(=NO)c3nccnc3Cl)c(F)c2F)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(c2c(CO)cc3c(-c4nccnc4Cl)noc3c2F)C[C@H](C)O1
Yield: 88.1 %

Procedure:
{5-[(3-chloropyrazin-2-yl)(hydroxyimino)methyl]-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-difluorophenyl}methanol (Intermediate 198, 106 mg, 0.26 mmol) in MeCN (4 mL) was treated with K2CO3 (53.2 mg, 0.39 mmol) at 120° C. for 1 hr. The mixture was diluted with EtOAc and washed with water and brine. The EtOAc solution was dried over anhydrous sodium sulfate, filtered and concentrated to afford 90 mg of product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:14])(=[O:25])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
First step: To a stirred solution of commercially available (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (8.78 g, 44 mmol) in CH2Cl2 (80 mL) at 0° C. were added Et3N (12.15 mL, 88 mmol) and methanesulfonyl chloride (5.09 mL, 66 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (50 mL) and TFA (15 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 2.63 g (34%) of (R)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.OCCC(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1>>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Agent: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Product: N#Cc1c[nH]c2ccc(C(CCO)c3ccccc3)cc12

Procedure:
5-(3-Hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LXV (1.24 g, 79%) was prepared from 3-(3-cyano-1H-Indol-5-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for 4-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (see Example 14).