Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH3:22])[N:13]=[C:12]([CH3:23])[CH:11]=1)(=O)C.Cl>CO>[ClH:21].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:23])=[N:13]2)=[C:16]([CH3:22])[CH:17]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(Cl)cc1C
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccc(Cl)cc2C)n1

Procedure:
1-Acetyl-2[1-(4-chloro-2-methylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (10.0 g.) was treated with HCl in methanol as described in Example II to give 7.4 g. product as the HCl salt, mp 134°-135°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1F
Temperature: 55 °C
Yield: 102.4 %

Procedure:
To an oven dried round bottom flask with stir bar was added 4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), (R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL). To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 18 hours. Reaction mixture was filtered through a pad celite, washing the solids with CH2Cl2. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol, 103% yield). 1H NMR (400 MHz, CDCl3) δ 1.27 (s, 9H) 7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9 (M+H)+, Rt 1.01 min.
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[S:7])[NH:5][NH2:6].[C:8]([O:15]CC)(=O)[C:9](OCC)=[O:10]>C(O)C>[SH:7][C:4]1[N:3]([CH3:2])[C:9](=[O:10])[C:8]([OH:15])=[N:6][N:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC(=S)NN
Agent: [Na]
Solvent: CCO
Product: Cn1c(S)nnc(O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 22 liter (l.) flask containing 12.5 l. of anhydrous ethanol maintained in a nitrogen atmosphere were slowly added 230 g. of sodium. The mixture was maintained at room temperature overnight, a slow, but constant, stream of nitrogen being admitted to the flask. The mixture then was heated to 50° C., and 1050 g. (10 mole) of 4-methylthiosemicarbazide were added. The temperature of the mixture fell to 40° C. To the mixture were then added 1530 g. of diethyl oxalate through a funnel. Addition was at a rate sufficient for the reaction mixture to attain a temperature of from about 60° C. to about 65° C. The temperature of the resulting mixture rose to 65° C. The mixture was refluxed with stirring for four hours during which time a precipitate formed. The precipitate changed in appearance during the period of reflux. Upon discontinuing heating and stirring, the white solid grandually settled to the bottom of the flask leaving a clear light yellow supernatant liquid. The mixture was allowed to stand overnight. The bulk of the clear supernatant was removed by suction, and the white crystalline product in the form of its sodium salt was removed from the residual mixture by filtration and washed with dry ethanol.
Reaction SMILES: [ClH:1].FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:9][C:10]1[C:15]2=[C:16](C)[C:17](OCCN3CCOCC3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(N)=O>[Cl:1][C:16]1[CH:17]=[CH:18][N:14]2[C:15]=1[C:10](=[O:9])[NH:11][CH:12]=[N:13]2
Reactant: Cl
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Solvent: NC=O
Product: O=c1[nH]cnn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (10.0 g, 57.3 mmol, WO 03/099286: Compound A of Example 9) in formamide (40 mL) was heated at 170° C. for 1 h and then at 190° C. for 1 h. Upon cooling to room temperature, the mixture solidified. The product was purified by recrystallization from ethyl acetate to give the title compound (6.53 g, 67%) as a white solid. 1H NMR (CDCl3) δ 10.24 (br s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.29 (d, 1H, J=2.8 Hz), 6.47 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 170.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=12.Cl[C:13]1[O:14][C:15]2[C:16](=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=2)[N:17]=1>C1COCC1>[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:13]3[O:14][C:15]4[C:16](=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=4)[N:17]=3)[CH2:8][C:7]=12
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N3CCn4ccnc4C3)nc12
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 0.130 g, 3.25 mmol) in THF (10 mL) was added 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.33 g, 2.71 mmol) and the reaction mixture stirred for 10 min. Methyl 2-chlorobenzoxazole-4-carboxylate (478 mg, 2.26 mmol), in THF (10 mL) was added and the reaction mixture was allowed to stir at room temperature 17 h. The reaction mixture was quenched with CH3OH (3 mL), and adsorbed onto silica gel (2 g). The crude product was purified by column chromatography (silica gel, 0.5 to 10% CH3OH in CH2Cl2) to afford methyl 2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzoxazole-4-carboxylate (251 mg, 37%) as an orange oil. 1H NMR and MS consistent.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[N:23]([CH3:30])[C:22]=2[CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[CH:27]1([CH2:26][C:24]2[N:23]([CH3:30])[C:22]3[CH:31]=[C:18]([N:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]5[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]4=[O:14])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:29][CH2:28]1
Reactant: Cn1c(CC2CC2)nc2ccc(Br)cc21
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(CC2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 150 °C
Yield: 37 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (91 mg), 6-bromo-2-(cyclopropylmethyl)-1-methyl-1H-benzimidazole (165 mg), N,N′-dimethylethylenediamine (0.045 ml)-, copper iodide (79 mg), potassium carbonate (229 mg) and DMSO (3 ml) was heated at 150° C. for 2 h under microwave irradiation. After cooling, the reaction mixture was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was washed with EtOAc and dried to give the title compound (62 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:19](=[O:20])[C:4]=2[CH:3]=1)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3.C(=O)(O)[O-].[Na+].[I-].[K+].[CH2:30](Br)[C:31]#[CH:32]>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:19](=[O:20])[C:4]=2[CH:3]=1)[CH2:14][CH2:15][N:16]([CH2:32][C:31]#[CH:30])[CH2:17][CH2:18]3
Reactant: C#CCBr
Reactant: O=C1c2cc(Cl)ccc2Sc2ccccc2C12CCNCC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCC2(CC1)C(=O)c1cc(Cl)ccc1Sc1ccccc12

Procedure:
A mixture of 2.5 g of 2-chloro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], free base of Example 5, 2.5 g of sodium bicarbonate, 2.0 g of potassium iodide and 1.1 g of propargyl bromide in 30 ml of dimethylformamide is treated according to the procedure of Example 16 to provide 2-chloro-10,11-dihydro-11-oxo-1'-(2-propynyl)spiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:18][CH2:17][CH2:16]2.O.[C:29]([O:33]C)(C)(C)C>FC(F)(F)C(O)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[CH:29]=[O:33])[C:19]([CH3:27])([C:23]([F:26])([F:24])[F:25])[O:18][CH2:17][CH2:16]2
Reactant: COC(C)(C)C
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C=O)C(C)(C(F)(F)F)OCC2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To hexamethylenetetramine (31.3 g, 223 mmol) was added trifluoroacetic acid (400 mL) and the mixture was heated to 70° C. for 90 minutes. A solution of 6-methoxy-1-methyl-1-trifluoromethyl-isochroman (50.0 g, 203 mmol) in trifluoroacetic acid (100 mL) was then added to the reaction mixture over 40 minutes. The solution was stirred for 3 hours and water was added (450 mL). The reaction mixture was stirred 16 hours, cooled to room temperature, and poured into methyl tert-butyl ether (500 mL). The organic layer was separated and washed with water (3×300 mL). The organic layer was poured into a round bottom flask and cooled to 0° C. 6N Sodium hydroxide was added in portions until the pH raised to 10 (˜500 mL). The organic layer was separated, washed with water (200 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde as an oil (54.2 g of a 12:1 mixture of regioisomers, 97%). 1H NMR (400 MHz, CDCl3) δ1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1), 3.97 (s, 3), 4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1). 13C NMR (75 MHz, CDCl3) δ23.07, 29.98, 55.73, 60.83, 76.03 (q, J=27.4), 111.81, 112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06, 160.89, 188.92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm−1. Analysis calculated for C13H13F3O3: C, 57.13; H, 5.05. Found: C, 56.94; H, 4.78.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:67]1([NH2:77])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](=[O:32])[NH:77][C@H:67]1[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
To a solution of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (7.5 g, 16.593 mmol) in DMF (100 mL) were added HATU (6.93 g, 18.252 mmol) and DIPEA (14.36 mL, 82.965 mmol) and the mixture was cooled to 0° C. (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (2.44 g, 16.593 mmol) was added dropwise and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to afford the title compound as an off white solid (9.6 g) which was used without purification. LC-MS: 582 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncc(O)cn1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25 mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). The thick mixture was stirred at room temperature for 1 h. To this was added a solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL) and the reaction was stirred at RT overnight under Ar. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic phase was separated and the aqueous was extracted with EtOAc (100 mL). The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine (100 mL) and then dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid (592 mg, 32%). MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([O:15][C:16]1[CH:38]=[CH:37][C:19]2[C:20]3[N:24]([CH2:25][CH2:26][O:27][C:18]=2[CH:17]=1)[CH:23]=[C:22]([C:28]1[N:29]([CH:34]([CH3:36])[CH3:35])[N:30]=[C:31]([CH3:33])[N:32]=1)[N:21]=3)([CH3:14])[CH2:12][OH:13])C1C=CC=CC=1>[Pd].[OH-].[OH-].[Pd+2]>[CH:34]([N:29]1[C:28]([C:22]2[N:21]=[C:20]3[N:24]([CH2:25][CH2:26][O:27][C:18]4[CH:17]=[C:16]([O:15][C:11]([CH3:14])([CH2:10][CH2:9][OH:8])[CH2:12][OH:13])[CH:38]=[CH:37][C:19]=43)[CH:23]=2)=[N:32][C:31]([CH3:33])=[N:30]1)([CH3:36])[CH3:35]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CCOCc4ccccc4)cc2OCC3)n(C(C)C)n1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CCO)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
To a solution of 4-benzyloxy-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutan-1-ol (29 mg, 0.0568 mmol) in IMS (5 mL) was added 10% Pd/C (5 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 4 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. To a solution of the residue thus obtained in IMS (5 mL) was added Pd(OH)2/C (10 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutane-1,4-diol as a colorless gum (14 mg, 56%). LCMS: RT 2.39 min [M+H]+ 428.3
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:36][CH2:35]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)O)cc12
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(C[C@H](C)N4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-isobutoxy-1H-indole-2-carboxylic acid, 80 (see example 8) and amine 50.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:30][N:31]1[C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][N:33]=[CH:32]1>>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:35]5[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl
Product: Cn1cncc1-c1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)amine hydrochloride and (3-methyl-3H-imidazol-4-yl) tri-n-butylstannane; δH [2H6] DMSO 11.85(1H,bs), 9.25(1H,s), 9.19(1H,s), 9.02(1H,d), 8.93(1H,s), 8.16(2H,d), 8.06(2H,d), 7.78(1H,d), 7.61(1H,dd), 7.22(5H,m), 5.66(2H,s) 3.92 (3H,s); m/z (M+1+) 432.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[CH:13]=[C:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][C:14](=[CH:13][CH2:12][OH:11])[CH2:15][CH2:16]1
Reactant: COC(=O)C=C1CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCC=C1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
DIBAL 1 M in methylene chloride (76.9 mL, 76.9 mmol) was added to a solution of (tetrahydro-pyran-4-ylidene)-acetic acid methyl ester (4.0 g, 25.6 mmol) in methylene chloride (100 mL) under nitrogen atmosphere cooled to −78° C. The reaction was stirred for 1 h, allowed to warm to room temperature, and stirred for an additional 2 h. The reaction was cooled to 0° C. and slowly quenched with methanol (35 mL). The reaction was vigorously stirred with water (35 mL) and Na2SO4 (170 g) for 30 minutes at room temperature. The resulting slurry was filtered and concentrated to give 2-(tetrahydro-pyran-4-ylidene)-ethanol (3.2 g, 97%) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.CN(C=O)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38](Cl)=[O:39]>O>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1)=[O:39]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCc2c(cccc2N2CCN(C(=O)c3ccc(Cl)c(Cl)c3)CC2)N1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 4 ml of DBU were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 3.0 g of 3,4-dichlorobenzoyl chloride. After completion of addition, the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 1.2 g of 5-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 250°-252° C., colorless powders.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37][CH3:38])[CH:28]=4)[CH:24]=[C:23]([CH3:39])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:38][O:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([CH3:39])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[CH:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:36])([F:34])[F:35]
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)c2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)c2)ccc1C(F)(F)F
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To N-tert-butyl-3-[4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 336) (0.277 g, 0.5 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.250 g, 100%). MS (ISP) 500.2 [(M+H)+]; mp 233° C. (dec.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]([S:11]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:2]1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]([S:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)C2=Cc3ccccc3OC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(C1=Cc2ccccc2OC1)N1CCNCC1

Procedure:
1-(2H-Benzopyrane-3-sulfonyl)-4-(tert-butoxycarbonyl)piperazine was treated with 4N hydrochloric acid in ethyl acetate to give a colorless solid of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH2:17])[CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC([OH:30])=C(C(C)(C)C)C=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:30]1)=[O:18]
Reactant: C=C(C(=O)OC)C(O)CCCCc1ccccc1
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: COC(=O)C1(C(O)CCCCc2ccccc2)CO1

Procedure:
A solution of 11.2 g (45 mmol) of β-hydroxy-α-methylenebenzeneheptanoic acid methyl ester in 300 ml of 1,2-dichloroethane is treated with 200 mg of 4,4'-thiobis(6-t-butyl-m-cresol) and 24.5 g (138 mmol) of m-chloroperoxybenzoic acid. The mixture is heated to reflux under nitrogen for 26 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]Cl.[CH2:14]([NH2:17])[CH2:15][CH3:16]>>[CH2:14]([NH:17][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:8]=1[Cl:13])[CH2:15][CH3:16]
Reactant: ClCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCN
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Into a 1-liter glass reactor, which could withstand a pressure of 6 atmospheres, fitted with a stirrer, heating mantle and a pressure gauge, were added 270.8 g 2-(2,4,6-trichlorophenoxy) ethyl chloride and 350 g n-propyl amine. The mixture was slowly heated with stirring over a period of 8 hours at a temperature of 90° C. The initial pressure under these conditions was 3 atmospheres, which dropped during the reaction to about 2.2 atmospheres. The end of the reaction was determined by GLC. At the end of the reaction the mixture was cooled to 55° C., whereupon the pressure dropped to atmospheric. The excess n-propyl amine was distilled off and it could be recycled for use in a subsequent batch, until a bottom temperature of 85° C. was reached. At the end of the distillation the mixture was cooled to 40° C., 300 ml of a 20% hydrogen chloride solution and 1 g of an emulgator GAF RM-510 were added. The temperature rose to 70° C., the mixture was stirred for one hour at this temperature and the product precipitated as white crystals of the amine hydrochloride salt. The slurry is cooled to 40° C., filtered, re-slurried in 250 ml xylene and filtered again. This affords 312 g of white hydrochloride salt of N-n-propyl-N-2-(2,4,6-trichlorophenoxy)-ethyl amine in 93% yield and purity of 96%-98%.