Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(S(O[C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:29])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=O)=O)(F)F.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.C[N:69](C)[CH:70]=[O:71]>[Pd](Cl)Cl>[CH3:28][O:27][C:26]1[C:9]([C:70]([NH2:69])=[O:71])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:29]
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(cc1C(N)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
A 1-L 3 neck round-bottomed flask equipped with an overhead stirrer, reflux condenser, nitrogen inlet and thermocouple, was charged with 2-methoxy-17-oxoestra-1,3,5(10)-triene-3-yl(trifluoromethyl)sulfonate (Scheme 5, Compound 42) (15 g, 34.7 mmol), 1,3-bis(diphenylphosphino)propane (1.54 g, 3.73 mmol), palladium (II) chloride (0.33 g, 1.9 mmol), 1,1,1,3,3,3-hexamethyldisilazane (31 mL, 150 mmol) and anhydrous dimethylformamide (110 mL). Carbon monoxide was bubbled through the yellow solution while stirring for 5 minutes. The reaction was heated to 110° C. under an atmosphere of carbon monoxide (balloon) and allowed to stir for 15 h. During this period the reaction became dark. The reaction was quenched by treating with methanol (25 mL) and stirred for 10 min. The mixture was poured into ethyl acetate (1 L) and washed with 2N sulfuric acid (750 mL). The aqueous layer was extracted with ethyl acetate (2×500 mL) and the combined organic phases were washed with 2N sulfuric acid (250 mL) and saturated aqueous sodium bicarbonate (500 mL) then dried over 500 g of sodium sulfate. This mixture was suction-filtered through a bed of silica gel 60 (67 g) and concentrated to dryness affording crude product (11.2 g, 98% recovery). The crude material was purified by Flash column chromatography (360 g of silica gel 60, eluting with methylene chloride, then 1:5 ethyl acetate:methylene chloride). Concentration of the pure fractions (Rf=0.3, 1:5 ethyl acetete:methylene chloride, UV detection) and drying in a vacuum oven at 50° C., and removal of residual solvents afforded pure product (Scheme 5, Compound 54) (4.97 g, 44% yield) as an off-white to pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.82 (br s, 1H), 7.05 (s, 1H), 5.92 (br s, 1H), 4.02 (s, 3H), 3.05 (dd, 2H, J=5), 2.15 (m 2H,) 2.02-1.65 (m, 6H), 1.55-1.15 (m, 8H), 0.80 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 220.6, 167.2, 155.9, 145.5, 132.8, 129.4, 118.3, 108.4, 55.9, 50.5, 47.9, 44.9, 37.8, 35.8, 31.6, 28.26, 26.4, 25.8, 21.6, 13.8.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:30])=C)[CH:23]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[C:13]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH2:30])[CH:23]=2)[CH3:20])=[CH:2][CH:1]=1)([CH3:12])([CH3:31])[CH3:32]
Reactant: [Li]CCCC
Reactant: C=C(C)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=Cc1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Methyl triphenylphosphonium bromide (1.07 g; 3.00 mmol) was added to benzene (20 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.9 ml; 3.00 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 5 (0.59 g; 2.00 mmol) in benzene (15 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with 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 (n-hexane:ethyl acetate=20:1), to thereby yield 0.29 g of the target compound as pale yellow oily matter (yield: 49.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10](OC)=[O:11])=[C:4]([N+:14]([O-])=O)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:8][CH2:9][C:10](=[O:11])[NH:14]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CNc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CNc2ccc(F)cc2N1
Temperature: 100 °C

Procedure:
Methyl N-(4-fluoro-2-nitrophenyl)glycinate (40 g, 175 mmol) in water (2000 mL) was heated to 90° C. Sodium dithionite (243.8 g, 1401 mmol) was added in portions. The resulting mixture was heated at 100° C. for 2 h, then allowed to cool. The solid was filtered off, washed with water and dried to give the product (13.75, 47%). Concentration of the liquor by evaporation to ˜700 mL gave a further precipitate which was filtered off, washed and dried as before to give more product (1.90 g: total yield 15.65 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[CH3:7].C([N:14]([CH:17]([CH3:19])[CH3:18])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:14][CH:17]2[CH2:19][CH2:18]2)=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1sc(C(=O)O)cc1Br
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1sc(C(=O)NC2CC2)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Bromo-5-methylthiophene-2-carboxylic acid (1.05 g, 4.75 mmol) was suspended in thionyl chloride (4.75 mL) and heated to 70° C. for 1.5 h. The mixture was concentrated and dried azeotropically with toluene. The reaction mixture was dissolved in dioxane (11.9 mL) to which diisopropylethylamine (4.14 mL, 23.7 mmol) and cyclopropylamine (1.36 mL, 23.7 mmol) were added and stirred at RT for 2 h. The reaction mixture was diluted with 50 mL ethyl acetate, partitioned with sodium bicarbonate (saturated, aqueous), and the organic layers were washed 2×50 mL with sodium bicarbonate (saturated, aqueous), washed with 3 N HCl, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 262 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[N:31][CH:32]=1>>[F:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Fc1ccc(Br)cn1
Product: Fc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-fluoropyridine (237 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (470 mg, 69%). MS (ISP) 451.1 [(M+H)+]; mp 213-216° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13](=O)[CH:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:1][C:2]3=[N:6][CH:5]=[CH:4][N:3]3[C:13]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Reactant: Sc1ncc[nH]1
Product: CS(=O)(=O)c1ccc(-c2sc3nccn3c2-c2ccccc2)cc1

Procedure:
Following the procedure of example 17, the title compound was prepared from 2-mercaptoimidazole and the bromoketone of step 3, example 1. 1H NMR (CDCl3): δ3.03 (s, 3H), 7.33 (d, 2H, J=3.5 Hz), 7.4-7.5 (m, 7H), 7.81 (d, 2H, J=8.4 Hz).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:26]([CH3:28])[CH3:27])[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11])=O)(C)(C)C.[ClH:29]>CCO>[ClH:29].[NH2:8][C@@H:9]([CH:26]([CH3:27])[CH3:28])[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.9 g, 4.85 mmol, Eq: 1.00) in EtOH (10.1 mL) was added HCl (2 M in ether, 38.0 mL, 76.0 mmol, Eq: 15.7) and the resulting solution was stirred at rt overnight. The reaction mixture was concentrated in vacuo and azeotroped with n-heptane (1×75 mL) to give (S)-ethyl 1-((S)-2-amino-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride as a white solid (1.6 g).
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:49][CH2:50][N:51]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:52][CH2:53]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:55])=[O:56])[CH:34]=2)[CH:30]=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)cc4)cnc32)cc1
Yield: 71.42 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was mesylated with methane sulfonyl chloride (17 mg, 0.148 mol) using triethylamine (35 μL, 0.247 mmol) in DCM (5 mL) to afford 60 mg (71.42% yield) of the titled compound. MS: m/z=685.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:27]Cl)[C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]2[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.[NH3:29]>C(O)C>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)=[C:6]([CH2:27][NH2:29])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cc(-c2ccnn2C)c2cccc(OCc3c(Cl)cncc3CCl)c2n1
Reactant: N
Solvent: CCO
Product: Cc1cc(-c2ccnn2C)c2cccc(OCc3c(Cl)cncc3CN)c2n1

Procedure:
Conversion of {5-chloro-4-[2-methyl-4-(2-methyl-2H-pyrazol-3-yl)-quinolin-8-yloxymethyl]-pyridin-3-yl}-methanol into the corresponding chloride according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine yielded the benzylchloride which was used in the following step without further purification. A solution of 8-(3-chloro-5-chloromethyl-pyridin-4-ylmethoxy)-2-methyl-4-(2-methyl-2H-pyrazol-3-yl)-quinoline (6.2 mg, 0.015 mmol) in a 2 M NH3 in ethanol (0.3 mL) was stirred at 45° C. for 2 h. Solvents were evaporated to dryness and the residue was used in the following step without further purification. MS (m/z): 394.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[S:16].CCCCCC.C1COCC1>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:15]([SH:16])=[N:14][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
[6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine (1.0 g, 5.3 mmol) and 1,1′-thiocarbonyldiimidazole (1.08 g, 6.1 mmol) were combined in DMF (10 mL) and heated at 50° C. for 2 h. After such time the mixture was allowed to cool to room temperature. Hexane (10 mL) was added followed by THF (4 mL), stirred for 10 mins then filtered and washed with THF (2 mL then 4 mL). Solid dried in vacuo to return 738 mg of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (60% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[CH:9]=1)([CH3:7])[CH3:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)(C)C(=O)CN)ccc1F
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a mixture of 1-amino-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one hydrochloride (35.4 g, 0.135 mol) and 4-fluorophenyl isothiocyanate (21.75 g, 0.142 mol) in DCM (500 mL) was added Et3N (37.6 ml, 0.27 mol) at 0° C., and the reaction mixture was warm to room temperature over 1 h. The reaction mixture was washed with 1N HCl (500 mL), satd NaHCO3 (500 mL) and brine (500 mL) successively, dried over MgSO4, filtered and concentrated under reduced pressure give a residue, which was triturated with Hex-EtOAc to afford 1-(3-(4-fluoro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)thiourea (45 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (b, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 7.05 (m, 1H), 6.79 (m, 2H), 6.67 (b, 1H), 3.88 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:31]=[O:32]>O>[Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C1CCc2c(cc3cc[nH]c3c2Br)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCN(CCC)C1CCc2c(cc3c(C=O)c[nH]c3c2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (9-Bromo-5,6,7,8-tetrahydro-1H-benzo[f]indol-6-yl)-dipropyl amine (50 mg, 0.14 mmol) in N,N-dimethyl formamide (3 mL) was cooled to 0° C. To this solution was added a cooled solution of phosphorus oxychloride (26 μL, 0.28 mmol) in N,N-dimethyl formamide (1 mL), which had been prepared 20 minutes previous to use. The mixture was stirred at ambient temperature for 30 minutes and then for 30 minutes at 50° C. an additional 30 minutes. The reaction mixture was then treated with a 1M sodium hydroxide solution (5 mL) with heating and stirring maintained for an additional hour. After cooling, the solution was diluted with water (25 mL) and extracted with several portions of diethyl ether. The combined etheral extracts were washed with water, brine, dried over magnesium sulfate, and the solvent evaporated. The residue was chromatographed on a silica column, using methanol as the eluant. This was then repeated with diethyl ether as eluant. The yield of the pure title compound was 50 mg (95%).:
Reaction SMILES: C(C1C=CC(C=CC(NCC(N(C2C(Cl)=C(C(Cl)=CC=2)CO[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)C)=O)=O)=CC=1)(O)=O.Cl.C(N)C.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:31]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)O)cc4)c3Cl)c2n1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 367.6 %

Procedure:
To a mixture of 8-[3-[N-(4-carboxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), ethylamine hydrochloride (16.9 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.2 mg) and 1-hydroxybenzotriazole (30.4 mg), and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride-methanol) to give 8-[2,6-dichloro-3-N-[4-(ethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (91 mg).
Reaction SMILES: [OH:1][P:2]1(=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>>[Cl:15][P:2]1(=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=P1(O)CCCc2ccccc21
Product: O=P1(Cl)CCCc2ccccc21

Procedure:
1-Hydroxy-1-oxo-1,2,3,4-tetrahydrophosphinoline (2.7g, 15 mmole) was refluxed with redistilled thionyl chloride (12 ml, 170 mmole) for 2 hr, and the excess of thionyl chloride removed by distillation. Distillation of the residue (bulb to bulb) at 150°/0.005 mm gave 1-chloro-1-oxo-1,2,3,4-tetrahydrophosphinoline (34), a light yellow fuming solid (2.3g, 76%). This was used without further purification.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1

Procedure:
A solution of 1,1-dimethylethyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 101) (1.34 g, 4.08 mmol) in N,N-dimethylformamide (11 ml) was degassed under vacuum (3 mm Hg) for 15 min then stirred under nitrogen. Zinc cyanide (575 mg, 4.90 mmol) then tetrakis(triphenylphosphine) palladium(0) (472 mg, 0.41 mmol) were added and the resulting mixture was stirred at 100° C. under nitrogen overnight then diluted with ethyl acetate. The insoluble residues were filtered off and washed with ethyl acetate, bleached for two days washed twice with brine, dried over magnesium sulphate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with 15-45% ethyl acetate in cyclohexane gave the title compound as a colourless solid (980 mg). MS (ES) C15H18N2O3 requires 274 found 275 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].Cl>O1CCCC1.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]3=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cnc3c(ccn3COCC[Si](C)(C)C)c2)OC1(C)C

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.01 g) was dissolved in tetrahydrofuran (10 ml). After the atmosphere was replaced with nitrogen, the solution was ice-cooled. 55% Sodium hydride (216 mg) was added and the mixture was stirred under ice-cooling for 20 minutes. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (875 μl) was added and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was diluted by adding water thereto, neutralized with 1 N hydrochloric acid (0.85 ml) and extracted with ethyl acetate three times. The organic layer was washed with water once and then with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The brown oil was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (691 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[S:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])[OH:32].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])(O)(=O)=O.[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:10](=[O:32])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (65 mg, 1.01 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (124 mg, 0.716 mmol) at 0° C. and the resulting mixture was stirred at room temperature for two hours. To reaction solution was added an aqueous sodium hydrogensulfate solution, the organic layer separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 50 mg (yield: 22%) of the title compound. Melting point: 195-196° C. (ethyl acetate-hexane).