Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([NH:32][CH3:33])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([NH:32][CH3:33])=[O:31])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:5]([Cl:15])=[N:4][CH:3]=1.O1CCCC1>C(O)C.[Pt].[S]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([Br:1])=[CH:3][N:4]=[C:5]2[Cl:15]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncc(Br)c12
Agent: [Pt]
Agent: [S]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc2c(Cl)ncc(Br)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.1 %

Procedure:
A solution of 4-bromo-1-chloro-5-nitroisoquinoline (14.0 g) prepared according to the method described in a known literature (Nair et al., Indian J. Chem., 1967, 5, 403) in ethanol (75 ml) and tetrahydrofuran (75 ml) was added with 3% platinum-sulfur/activated carbon (3% Pt—S/C, NE Chemcat, CM101, 14.0 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen gas atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble solids were removed by filtration through Celite, and the solvent was evaporated under reduced pressure to obtain the title compound (12.8 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[O:1]=[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2cccnc2n(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
2.00 g (6.8 mmol) of ethyl 2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (100 mL), and 1.41 g (10.2 mmol) of potassium carbonate and 200 mL of water were added thereto at room temperature. The resulting mixture was stirred for 3 hours at 50° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in water. Concentrated hydrochloric acid was added thereto to make the solution acidic. A solid precipitated therefrom was separated by filtration, and was dried. Thus, 1.72 g of the title compound was obtained as pale yellow crystals (yield: 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].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.C1(C)C=CC=CC=1>[CH2:31]([O:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:32]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
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: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (20 g), 4-(2-ethoxyethoxy)phenyl borate (14.9 g), 1M potassium carbonate solution (130 ml), ethanol (130 ml) and toluene (1000 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (3 g), and the mixture was refluxed under argon atmosphere for 15 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (25.2 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)C1C=CC=CC=1.NC1C=CC=CC=1N>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Agent: Nc1ccccc1N
Solvent: O=Cc1ccccc1
Product: COc1ccc(CC[N+](=O)[O-])cc1
Yield: 92 %

Procedure:
Example 227 A) 4-Methoxy-β-nitrostyrene (25.0 g, 0.15 mole) was reacted with benzaldehyde (19.1 g, 0.18 mole) and 1,2-diaminobenzene (19.8 g, 0.18 mole) according to the procedure of Chikashita et. al. (Synth. Commun. 1985, 15 (6), 527) to yield methoxy-4-(2-nitroethyl) benzene (25.0 g, 93%) as a yellow oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
3.46 g (15 mmoles) of BOC-Leu-OH are dissolved in 50 ml of ethyl acetate, 2.1 ml (15 mmoles) of triethylamine are added, and the solution is cooled to -15° C. The mixture is stirred at the same temperature, and 1.97 ml (16 mmoles) of pivaloyl chloride are added dropwise, followed by 1.65 ml (16.5 mmoles) of piperidine. The mixture is stirred for 10 minutes between the introduction of the two reactants. When the addition is complete, the mixture is stirred for additional 30 minutes at -10° C., and then it is allowed to stand in a refrigerator overnight. The separated precipitate is filtered off, the filtrate is washed thrice with 10 ml of n hydrochloric acid, each, thrice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is dissolved in 15 ml of a 4 n solution of hydrochloric acid in ethyl acetate, the mixture is allowed to stand for one hour, then it is diluted with ether and stored in a refrigerator overnight. The precipitate is filtered off to obtain 2.0 g (57%, calculated for BOC-Leu-OH) of H-Leu-piperidine.HCl; m.p.: 123°-125° C., Rf5 =0.45.
Reaction SMILES: CS(C1C=CC(C2C=CC(C(=C3CC(C)(C)CC(C)(C)C3)C3C=CC(O)=CC=3)=CC=2)=CC=1)(=O)=O.Br[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[C:50]2[CH2:55][C:54]([CH3:57])([CH3:56])[CH2:53][C:52]([CH3:59])([CH3:58])[CH2:51]2)[C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.[C:60]([C:62]1[CH:67]=[CH:66][C:65](B(O)O)=[CH:64][C:63]=1[F:71])#[N:61].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.O.C1COCC1>[F:71][C:63]1[CH:64]=[C:65]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([C:43]3[CH:44]=[CH:45][C:46]([OH:49])=[CH:47][CH:48]=3)=[C:50]3[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]([CH3:56])([CH3:57])[CH2:55]3)=[CH:38][CH:37]=2)[CH:66]=[CH:67][C:62]=1[C:60]#[N:61]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(C#N)c(F)c3)cc2)CC(C)(C)C1
Yield: 71.9 %

Procedure:
The Suzuki protocol described for (163) was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.200 g, 0.5 mmol), PdCl2(PPh3)2 (0.035 g, 0.05 mmol), (4-cyano-3-fluorophenyl)boronic acid (0.165 g, 1.0 mmol), aqueous 2 M Na2CO3 (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H2O (5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 12 h. Regular work-up and purification gave 0.158 g (72%) of the title compound (237) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 7.96 (dd, J1=7.2 Hz, J2=7.2 Hz, 1H), 7.88 and 7.85 (dd, J1=11.2 Hz, J2=1.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 3H), 7.25 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 1.93 (s, 2H), 1.92 (s, 2H), 1.26 (s, 2H), 0.89 (s, 6H), 0.88 (s, 6H). LCMS (APCI): m/z 437.97 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[C:21]([F:36])=[CH:22][C:23]([CH:33]2[CH2:35][CH2:34]2)=[C:24]([N:26]2[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]2)[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[F:18][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:19][C:20]2[C:21]([F:36])=[CH:22][C:23]([CH:33]3[CH2:35][CH2:34]3)=[C:24]([N:26]3[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1NC1CCN2CCCC2C1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CCN5CCCC5C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)octahydroindolizin-7-amine (54 mg, 0.2 mmol), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5-one (52 mg, 0.21 mmol; prepared according to US20110130415 pages 43-48, which is hereby incorporated by reference in its entirety) and para-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 70° C. and stirred for 2 days. After cooling, the mixture was concentrated under vacuum to leave a crude residue. The residue was purified by preparative high-performance liquid chromatography to give a solid. The solid was partitioned between EtOAc (20 ml) and 1N NaOH (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml) and the combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave the product (46 mg, 47%) as a solid after freeze-drying from MeCN/H2O.
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]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]2)[CH:20]=1>CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2s1
Reactant: N[C@H]1CCN(Cc2cccnc2)C1
Agent: CN(C)c1ccncc1
Product: O=C(N[C@H]1CCN(Cc2cccnc2)C1)[C@@H]1CCCCN1c1nc2ccccc2s1

Procedure:
The title compound was prepared by a similar method to Example 1, excepting that a catalytic amount of 4-dimethylaminopyridine was also used, from (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 43] and (3S)-1-(3-pyridinylmethyl)pyrrolidine-3-amine [see Preparation 41] to afford (2S)-1-(1,3-benzothiazol-2-yl)-N-[(3S)-1-(3-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]CC5C=CC=CC=5)[CH:19]=4)[CH2:16][N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:14]3=[O:38])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:14]3=[O:38])=[CH:11][CH:12]=2)=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)CCN1CC(c2cccc(OCc3ccccc3)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)CCN1CC(c2cccc(O)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
To 3-(4-(4-chlorophenoxy)phenyl)-4-(3-(benzyloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one (Example 289) (200 mg, 0.35 mmol) in methanol/ethyl acetate (1:3) is added 20 mg Pd/C. The mixture is stirred under H2 atmosphere for 30 minutes. Filtration through a bed of celite and evaporation yields 178 mg of the title compound as a white solid. 1H NMR (CDCl3) δ 7.32-7.29 (m, 2H), 7.25-7.19 (m, 2H), 7.19-7.15 (m, 1H), 6.88-6.83 (m, 4H), 6.79-6.73 (m, 3H), 5.10 (dd, J=9.2, 5.6 Hz, 1H), 3.97-3.88 (m, 2H), 3.75-3.68 (m, 1H), 3.38 (dd, J=8.8, 6.0 Hz, 1H), 3.36 (t, J=6.4 Hz, 2H), 3.01 (s, 3H); HPLC-MS calculated for C24H23ClN2O5S (M+H+): 487.1, found 487.1.
Reaction SMILES: [C:1]([C:3](=[N:7][O:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].O1CCCC1.[H-].[Na+].[CH3:17][O:18][CH2:19][N:20]=[C:21]=[O:22]>C(O)(=O)C>[C:1]([C:3](=[N:7][O:8][CH3:9])[C:4]([NH:6][C:21](=[O:22])[NH:20][CH2:19][O:18][CH3:17])=[O:5])#[N:2]
Reactant: COCN=C=O
Reactant: CON=C(C#N)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCNC(=O)NC(=O)C(C#N)=NOC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2.70 g. of 2-cyano-2-methoxyiminoacetamide in 10 ml. of tetrahydrofuran was added 1.20 g. of a 55% suspension of sodium hydride in mineral oil in portions with stirring. After stirring for 15 minutes, 2.40 g. of methoxymethylisocyanate was added dropwise. The mixture was stirred at 50°C. for 3 minutes to ensure completion of the reaction. The mixture was then cooled in an ice bath, and a solution of 1.9 ml. of acetic acid in 120 ml. of ice water was added rapidly with stirring. After stirring for another 25 minutes, 2-cyano-2-methoxyimino-N-methoxymethylcarbamoylacetamide was collected on a filter, washed with water and ether, and dried. The product weighed 2.7 g. and melted at 163.5°-165°C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:31])=[CH:15][N:16]3[S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:9]=[C:8]([CH3:32])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>CN(C=O)C>[CH3:32][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:33]=[CH2:34])[N:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:31])=[CH:15][N:16]3[S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[CH:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1c(C)cc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc1Cl
Solvent: CN(C)C=O
Product: C=Cc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)cc(C)c1C(=O)OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-chloro-4-methyl-6-(3-methyl-1-tosyl-1H-indol-4-yl)nicotinate (0.348 g, 0.742 mmol) in DMF (5 mL) was sparged with argon for 10 min before trans-Pd(PPh3)2Cl2 (0.052 g, 0.074 mmol), tri-n-butyl(vinyl)tin (0.353 g, 1.11 mmol), and BHT (0.016 g, 0.074 mmol) were added. The resulting suspension was sparged with argon for 5 min and the vessel was sealed and heated at 60° C. After 24 h the reaction was allowed to cool to rt and 50% KF on Celite® was added. The resulting slurry was then filtered over Celite® eluting with EtOAc. The organic was then washed with 10% KF in water and then dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (5-40% EtOAc/heptane) to give the title compound. MS ESI m/z 461.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:18][C:17]3[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=3)[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: Fc1ccc(CCl)cc1
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2c(Cl)nccc12
Yield: 86 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 4-fluorobenzyl chloride, the titled compound was obtained as a pale yellow solid. (Yield: 86%)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: C=CCc1cc(Oc2ccc(Cl)cc2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1O
Yield: 99.6 %

Procedure:
A mixture of the product from step 4 (15.7 g, 60 mmol) and 10% Pd/C (3.1 g) in ethyl acetate (300 mL) was stirred under hydrogen (1 atm). After the reaction was completed (ca. 30 min), the mixture was filtered through celite and the filtrate was concentrated to give 15.7 g of the title compound as an oil which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:57]1[CH2:61][CH2:60][CH2:59][C@@H:58]1[CH2:62][N:63]1[CH:67]=[CH:66][N:65]=[CH:64]1.ClCl>O1CCCC1.ClCCl.CO>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:57]1[CH2:61][CH2:60][CH2:59][C@@H:58]1[CH2:62][N:63]1[CH:67]=[CH:66][N:65]=[CH:64]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1cn(C[C@H]2CCCN2)cn1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2Cn2ccnc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 50 %

Procedure:
Prepared analogously to Example 1g from 2-chloro-4-{N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (R)-1-(pyrrolidin-2-ylmethyl)-1H-imidazole in tetrahydrofuran. Yield: 50%; Rf value: 0.20 (silica gel: dichloromethane/methanol=9:1); C25H24C12N6O2 (511.415); mass spectrum: (M+H)+=511/513/515 (chlorine isotope).
Reaction SMILES: [C:1]([OH:7])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][NH2:14])[CH2:9][CH2:10][CH3:11]>CCCCCCC>[C:1]([NH:14][CH2:13][CH:12]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCCCCC(CN)CCCC
Reactant: CC(C)(C)C(=O)O
Solvent: CCCCCCC
Product: CCCCCCC(CCCC)CNC(=O)C(C)(C)C
Yield: 76 %

Procedure:
10.4 g of pivalic acid and 17.2 g of 2-butyloctylamine were mixed together in the tube of a microwave machine (Maxidigest™ MX 350 from the company Prolabo; frequency 2450±50 MHz, modulable power 300 W). After irradiation for about 1 hour at 160° C.±10° C., the reaction mixture was dissolved in heptane and then purified on silica. 19 g of the desired amide were obtained.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.F[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>O.C1(C)C=CC=CC=1>[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 87.5 °C

Procedure:
A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), and DMAC (550 mL) was heated to 75-100° C. Toluene (166 mL) was added, and the mixture was slowly heated to reflux at 134° C. The reflux temperature was raised by distillation of toluene and water into a water trap until the temperature reached 141° C. The mixture was then allowed to cool to below 100° C. at which point 4-fluorobenzonitrile (24.46 g, 202 mmol) was added along with 50 mL of toluene. The mixture was again heated to reflux at 140° C. with water being collected in a toluene-filled water trap for 4 h. The mixture was allowed to cool to room temperature, and the solids were filtered and rinsed with toluene. The filtrate was concentrated on a rotary evaporator to 77 g of syrup which was dissolved in EtOAc (400 mL). This solution was extracted with water (400 mL), and the aqueous layer was back-extracted with EtOAc (100 mL). The combined organic layers were washed with water (3×400 mL) and concentrated in vacuo to 53.4 g (100%) of oil which was >98% pure by HPLC analysis: 1H NMR (300 MHz, DM,)O-d6) NMR was consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N:23]([CH2:32][O:33][CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(COC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea 100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, chloromethyl methyl ether (67 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 18 mg (yield 18%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li:13]CCCC.C=CC=C.C=CC=C.C=CC1C=CC=CC=1>C1COCC1.C1CCCCC1>[Li:13][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: [Li]CCCC
Agent: C=CC=C
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: [Li]C1(c2ccccc2)SCCCS1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenyl-1,3-dithiane (2.1 g, 10.69 mmol) in THF (5 mL) and cyclohexane (10 mL) was added n-BuLi (6.37 mL, 1.68 M in hexane) dropwise via a syringe at −78° C. The solution was stirred for an additional 3 hours at 0° C. The resulting 0.5 M 2-litho-2-phenyl-1,3-dithiane (abbreviated as PDT-Li) was used for anionic initiator for polymerizing butadiene and/or butadiene/styrene and stored in an inert atmosphere of nitrogen in a refrigerator.