Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[C:17]2=[CH:18][N:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14]1.[Br:22][C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Br:22][C:23]1[C:24]([C:14]2[S:13][C:17]3=[CH:18][N:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1
Reactant: c1cc2ccsc2cn1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.02 mL, 7.27 mmol) was added to a flask containing anhydrous THF (10 mL) and the mixture, while kept under an atmosphere of nitrogen, was cooled to −78° C. n-BuLi (2.5 M in hexanes, 2.9 mL, 7.27 mmol) was added dropwise to the mixture, which was stirred for 30 min. Thieno[2,3-c]pyridine (0.82 g, 6.06 mmol) dissolved in anhydrous THF (10 mL) was added to the reaction mixture dropwise. The reaction was stirred at −78° C. for 10 min and then at −40° C. for 20 min. 5-Bromo-2-chloropyrimidine, dissolved in anhydrous THF (5 mL) was added to the reaction slowly. The mixture was allowed to stir at −40° C. for 2 h and then was quenched with a 1:1 mixture of acetic acid/methanol (5 mL). The mixture was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g, 6.66 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (50 mL) was added to the reaction mixture, which was stirred for an additional 5 min. The reaction was then diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by column chromatography using a gradient of 5 to 40% ethyl acetate in hexanes to obtain a light brown solid. Yield=0.5 g. MS (M+H)+ 326/328.
Reaction SMILES: [CH2:1]([C:8]1(O)[C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=2[O:10][C:9]1([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[CH2:1]([CH:8]1[C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=2[O:10][C:9]1([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Cc1ccccc1
Yield: 56 %

Procedure:
Using N-(3-benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 249, the title compound was synthesized in the same manner as in Example 271. Yield: 56%. Melting point: 186-187° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:20][CH2:19][C:18]4[C:14](=[CH:15][NH:16][N:17]=4)[CH2:13]3)[C:8]2=[O:21])=[C:4]([Cl:24])[CH:3]=1.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O>[Cl:24][C:4]1[CH:3]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([C:33]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:34])=[CH:40][CH:39]=2)[CH:23]=[CH:22][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:20][CH2:19][C:18]3[C:14](=[CH:15][NH:16][N:17]=3)[CH2:13]2)[C:8]1=[O:21]
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc(-c3ccc(CC4CCN(C5CCc6n[nH]cc6C5)C4=O)c(Cl)c3)cc2)CC1
Yield: 13 %

Procedure:
Dissolve 3-(4-Bromo-2-chloro-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 6) (0.471, 1.16 mmol) in DME (5.0 mL) and de-gas with a stream of nitrogen for 5.0 minutes. Add (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone hydrochloride (0.1.14 g, 1.58 mmol), followed by 2.0 M sodium carbonate (2.03 mL, 4.06 mmol) and continue de-gas. Add Pd(Ph3)4 (0.134 g, 0.116 mmol) and heat to 80° C. for 17 hours. Dilute with ethyl acetate and water, separate and save both layers. The pH of the aqueous layer adjusted to ph 9 with 1.0 N HCl, and back extract with three portions of ethyl acetate. The organic layers are combined, dry over sodium sulfate and evaporate. Chromatography (silica 95:5 CH2Cl2/MeOH/1% NH3) yields 0.08 g (0.6%) of the title compound as an amorphorous foam. MS (m/z): 533 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[N:27]=[CH:26]1>>[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:2]4[N:3]=[C:4]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[N:5]=[C:6]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=5)[C:7]=4[CH2:8][CH2:9]3)=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: Nc1ccc2[nH]cnc2c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc3[nH]cnc3c2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 1H-benzimidazol-5-ylamine, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:34]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([C:43](=[O:44])[C@@H:42]([NH:41][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:46]([CH3:48])[CH3:47])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol), (S)-2-(Boc-amino)-3-methylbutyric acid (0.28 g, 1.29 mmol) and 4-ppy (9 mg, 0.06 mmol) in DMF (2 mL) was added EDCI (234 mg, 1.23 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc (30 mL) and washed with water (30 mL×3). The mixture was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=3/1 to 2/1) to afford the title compound as a white solid (41 mg, 29.1%). The title compound was characterized by LC-MS as shown below:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]#[CH:25]>>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]#[CH:23]
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Reactant: C#CCBr
Product: C#CCOc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (100 mg, 0.45 mmol) and 3-bromoprop-1-yne (129 mg, 0.93 mmol) according to the general procedure IV to give 105 mg (72%) of a pure light brown oily product. Rf=0.56 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.46 (dt, J=6.3 Hz, 1.8 Hz, 2H), 7.28-7.25 (m, 1H), 7.19, 7.15 (m, 3H), 7.12 (dd, J=2.5 Hz, 1.3 Hz, 1H), 6.96 (ddd, J=8.3 Hz, 2.8 Hz, 1.0 Hz, 1H), 4.70 (d, J=2.5 Hz, 2H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.54 (t, J=2.4 Hz, 1H); 13C NMR (CDCl3): δ 173.1, 157.3, 141.0, 131.8, 129.4, 128.3, 125.0, 124.4, 121.0, 117.4, 115.6, 89.3, 88.8, 78.3, 75.7, 55.9, 51.6, 35.4, 30.8; MALDI-MS m/z 341.4 (M+Na+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].O>CN(C)C=O>[CH2:18]([NH:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 30 g of 6-(4-chlorobutoxy)-carbostyril, 103 ml of benzylamine and 33 g of sodium iodide in 300 ml of dimethylformamide was stirred at 80° C. for 8 hours. The reaction mixture was allowed to cool and then poured into water. The resulting precipitate was collected by filtration. The precipitate was washed with water and diethyl ether in this order to obtain 29.1 g of 6-(4-benzylaminobutoxy)carbostyril.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24].[Cl-].[NH4+]>ClCCl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23]([NH:12][CH:10]([CH3:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)=[O:24]
Reactant: CC(N)Cc1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Cl)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 24 h

Procedure:
100 mg of 1-(4-chlorophenyl)propan-2-amine hydrochloride (0.728 mmol) and 0.10 ml of triethylamine (0.728 mmol) are diluted in 3 ml of dichloromethane at room temperature, 152 mg of 2,6-dichlorobenzoyl chloride (0.728 mmol) are added to the reaction mixture. After 24 hours of stirring, 20 ml of DCM an 10 ml of saturated solution of ammonium chloride are added to the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[Cl:14].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:11])=[CH:7][C:6]=1[Cl:14]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(Oc2ccccc2Br)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3Br)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
4-(2-Bromophenoxy)-3-chlorobenzoic acid (174 mg, 0.53 mmol), 1-hydroxybenzotriazole (108 mg, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.8 mmol), triethylamine (0.4 mL, 2.88 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. To the mixture, water (20 mL) was added and the resultant mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(2-bromophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (190 mg, 78%). LRMS (M+H) m/z: calcd 460.02. found 460. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.44 (t, J=4.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.46-7.40 (m, 1H), 7.23-7.17 (m, 1H), 7.10 (dd, J=6.9 Hz, J=1.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.85 (s, 1H), 4.27 (d, J=4.5 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH3:20].C1(C)C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:16][O:15][C:13]([C:12]1[CH:17]=[CH:18][C:9]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:7])=[C:10]([O:19][CH3:20])[CH:11]=1)=[O:14]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Temperature: 105 °C
Yield: 99 %

Procedure:
A solution consisting of toluene (100 mL), ethanol (50 mL), and water (50 mL), was sparged with dry nitrogen gas for 45 minutes. To the solvent mixture was added 4-bromo-3-methoxybenzoic acid methyl ester of Step B (26.5 mmol), o-tolylboronic acid (29.1 mmol), and sodium carbonate (112.5 mmol). The mixture was sparged with nitrogen gas for an additional ten minutes. Tetrakis(triphenylphosphine)palladium(0) (1 mmol) was added to the mixture which was then heated at 105° C. for 6 hours. The mixture was cooled and the phases separated. The organic phase was washed three times with a sequence of saturated aqueous sodium carbonate, and brine. The organics were dried over anhydrous sodium sulfate, and evaporated to an oil. Chromatography on silica gel using dichloromethane and hexane (3:1) provided the title compound as a clear oil (6.7g, 99%).
Reaction SMILES: O1CC[C@@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@@H:36]([N:8]([CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: CCOCC
Reactant: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CN(C(=O)O)[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.04 h

Procedure:
To a solution of (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (0.085 g, 0.18 mmol) in 9 mL CH2Cl2 was added dropwise a 2.0 M HCl solution in ether (0.09 mL, 0.18 mmol). Ether (20 mL) was then added, leading to the precipitation of (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride which was filtered and dried (85 mg, 95%). LC/MS: m/z 463.5 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=CC=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-]>C(Cl)Cl>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31][CH:32]3[CH2:36][CH2:37][CH2:38][CH2:33]3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OC2CCCC2)O1

Procedure:
was prepared by a similar method as 213e, (74%) as a colourless solid: mp. 172-80° C.; [α]D23 −91.5° (c 0.1, CH2Cl2); IR (KBr) 3290, 1792, 1677, 1657, 1642, 1544, 1429, 1280, 1259, 1124, 977; 1H NMR (CDCl3) δ7.80 (2H, m), 7.46 (3.5H, m), 7.00 (1H, d, J=6.7), 6.48 (0.5H, d, J=7.9), 5.55 (0.5H, d, J=5.3), 5.19 (2H, s+m), 4.93 (0.5H, m), 4.62 (1.5H, m), 4.34 (1H, m), 4.18 (0.5H, m), 3.28-2.70 (4H, m), 2.49-2.29 (2H, m), 205-1.48 (15H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[4-Chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(dimethylamino)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc(NCCCCCO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(NCCCCCO)ccc1N

Procedure:
The 5-(4-nitro-3-methylphenylamino)pentan-1-ol (17) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1OCc1ccccc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-phenylmethoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.11 (2H, s), 5.27 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.98-7.00 (2H, m), 7.33-7.39 (7H, m), 7.55 (1H, d, J=2.0 Hz), 7.99 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H17ClN4O2, 417; Found, 417.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH3:26]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=2)[N:3]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.2 %

Procedure:
To a solution of 2,6-dichloro-3-trifluoromethylpyridine (1 g, 4.54 mmol) in a mixture of toluene (11 mL), 1,4-dioxane (5.88 mL), and water (5.88 mL) were added sodium carbonate (0.96 g, 9.07 mmol), 4-ethylphenyl boronic acid (0.61 g, 4.08 mmol), and PdCl2(dppf)CH2Cl2 (0.75 g, 0.92 mmol). The mixture was stirred at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.69 g, 53%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 8.15 (d, 1H), 8.01 (d, 2H), 7.95 (d, 1H), 7.33 (d, 2H), 2.71 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8](N(OC)C)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:1][C:2]1[C:3]([C:8]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nn(C)cc1Br
Solvent: C1CCOC1
Product: Cn1cc(Br)c(C(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of compound 4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide (1.0 g, 4 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere was added (4-chlorophenyl)magnesium bromide (8 mL) in tetrahydrofuran (1 M) at 0° C., The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by saturated solution of ammonium chloride, and dichloromethane (100 mL) was added, the separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give the titled product as a white solid (1.0 g, 84%). LC/MS m/z 298 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=9 Hz, 2H), 7.53 (s, 1H), 7.43 (d, J=9 Hz, 2H), 3.99 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[C:19]([N:8]1[C:7](=[O:23])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][O:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9]1(=[O:18])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(Cl)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-chlorophenol in a similar manner as described for Example 5. 1H NMR (500 MHz CDCl3): δ 7.54-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.26-7.20 (m, 2H), 6.82-6.76 (m, 2H), 5.72 (t, 1H), 3.86 (t, 2H), 3.11-3.06 (m, 2H), 1.88-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 157.1, 135.3, 131.8, 129.8, 129.6, 128.8, 126.2, 125.3, 115.9, 107.3, 66.4, 61.7, 42.4, 28.9, 27.8; Mass Spectrum: M+H+ 449.