Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.N1C=CC=CC=1.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: COC(CNCc1ccc(F)c(Cl)c1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
147.0 g (3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 540 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 145.8 g (1.04 mol) p-toluenesulfonylchloride in 200 ml of dichloromethane was added. After 5 h at room temperature additional 20 ml of pyridine, 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added. The solution was stirred at room temperature for 7 h and then refluxed for additional 4 h. Again 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added and the mixture was stirred overnight. For workup, the solution was washed twice with 2 N HCl and twice with saturated NaHCO3-solution. The organic layer was dried with MgSO4 and evaporated. Final silicagel chromatography (heptane/ethyl acetate 4:1) gave 155 g of the title compound as a yellow oil. Rt=1.80 min (Method B). Detected mass: 370.2 (M-OMe−).
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[N:21]=[CH:22][NH:23]5)[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (71.8 mg, 0.30 mmol), and DIPEA (0.153 mL, 0.90 mmol) in n-butanol (1.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 3 mL) was added and the mixture stirred at 0° C. for 1.5 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 405 as a white solid (72.8 mg, 69%). LCMS (Method K): RT 2.68 min [M+H]+ 352.0. 1H NMR ((CD3)2SO, 400 MHz): 12.93 (1H, bs), 8.24 (1H, s), 8.15 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.43 (1H, dd, J=8.7, 4.8 Hz), 6.99 (1H, dd, J=10.8, 8.8 Hz), 5.83 (1H, bs), 4.31-4.29 (2H, m), 3.04-3.01 (2H, m), 2.08-1.94 (4H, m), 1.66 (3H, d, J=6.7 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[CH2:34][NH:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=[C:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-1-(4-nitro-phenyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole (2.6 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16](C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[PH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=[PH2]c1ccccc1
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (150 ml.). Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 40°-60° C.). The solid thus obtained was recrystallised from petroleum ether (b.p. 60°-80° C.) to give hexanoylmethylenephenylphosphorane (17 g.), m.p. 73°-74° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): Reaction of 4.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 19.3 g of molecular sieve 5 A, 3.8 g of (D)-valine methyl ester hydrochloride and 1.43 g of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(D)-valine methyl ester after flash chromatography (N3). (TLC: N2) Rf : 0.56.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5]CCNC)=[O:4].CCN(C(C)C)C(C)C.[CH2:21]([O:28][C:29]([N:31]1[C:35](=O)[CH2:34]C[C:32]1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29](=[O:30])[N:31]([CH3:32])[CH2:35][CH2:34][NH:5][C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of compound A (96.8 g, 340.7 mmol) and DIEA (59.3 ml, 340.7 mmol) in THF (350 ml) was cooled to ˜5° C., followed by addition of a solution of N-(benzyloxycarbonyl)succinimide (84.0 g, 337.3 mmol) in THF (150 ml) dropwise over the period of 20 min The temperature of reaction mixture was raised to room temperature and stirring was continued for an additional 30 min, followed by the solvents being evaporated. The resultant residue was dissolved in EtOAc (600 ml). EtOAc was extracted with 5% aq. NaHCO3 (2×150 ml) and brine (150 ml). The organic layer was separated and evaporated to provide compound B as yellowish oil (103.0 g, 340.7 mmol). LC-MS [M+H] 305.3 (C13H15F3N2O3+H, calc: 305.3). Compound B was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.[F:15]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: FF
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: Fc1cc(Cl)c2ccc(Cl)cc2n1
Yield: 30.6 %

Procedure:
A solution containing 4,7-dichloroquinoline (1.0 g, 5 mmol) and iodine (1.28 g, 5 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture by volume in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added, the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to an oil (0.98 g). GC/MS analysis showed a 34% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-4,7-dichloroquinoline (0.33 g, 87%) as white crystals; other data were the same as that described in the following reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (800 mg) was dissolved in dichloroethane (16 ml), added with 1,2,3,4-tetrahydroquinoline (0.50 ml), sodium triacetoxyborohydride (1.7 g) and acetic acid (2.3 ml) and stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (20 ml) and extracted twice with ethyl acetate (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) to obtain 90.6 mg of the title compound. Yield: 7%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Yield: 51.9 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 92, 750 mg, 1.48 mmol), iron (495 mg, 8.86 mmol) and NH4Cl (55.3 mg, 1.03 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 4 h. Purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided part-purified material that was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (367 mg, 52%) as a yellow solid. Impure fractions containing desired product were concentrated in vacuo and the resulting residue was triturated with CH2Cl2/diethyl ether to give more of the title compound (230 mg, 33%) as a yellow solid. Total: 597 mg, 85%; 1H NMR: (CDCl3) 2.37 (3H, s), 2.56 (4H, br s), 2.95 (4H, br t), 3.75 (2H, br s), 3.84 (3H, s), 3.90 (3H, s), 6.70 (1H, s), 7.27-7.36 (2H, m), 7.38-7.42 (1H, m), 7.63 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.63-8.69 (1H, m); m/z: ES+ MH+ 478.55.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[C:33](Cl)(=[O:35])[CH3:34].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[C:33](=[O:35])[CH3:34])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.46 mg, 0.061 mmol), acetyl chloride (0.043 mL, 0.610 mmol), Hünig's base (0.159 mL, 0.915 mmol). The resulting mixture was stirred at room temperature. After 20 min, the solvent was concentrated and the crude product was purified by column chromatography (24 g of silica, 10 to 40% acetone in hexanes) to afford N-(1-methylethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide as a mixture of two isomers.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(N(C)C)cc2)cc1-c1c(Br)cnn1C
Reaction time: 48 h

Procedure:
To 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (34.9 mg, 0.124 mmol) in CH2Cl2 (3 mL) was added 4-(dimethylamino)phenyl isocyanate (21 mg, 0.129 mmol) and stirred for two days. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 116 as a waxy solid (13.5 mg, 25%). LCMS m/z (%)=444 (M+H79Br, 100), 446 (M+H81Br, 95), 1H NMR (400 MHz, DMSO-d6) δ: 8.51 (bs, 1H), 8.26 (bs, 1H), 7.61 (s, 1H), 7.53 (dd, J=8.97, 2.71 Hz, 1H), 7.34 (d, J=2.70 Hz, 1H), 7.24 (d, J=9.03 Hz, 2H), 7.12 (d, J=9.05 Hz, 1H), 6.68 (d, J=9.07 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H), 2.82 (s, 6H).
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>O>[C:11]([O:10][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CCCCCC/C=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC/C=C\COC(C)=O

Procedure:
Cis-2-nonenol (2.9 g, 0.03 mole), acetic anhydride (3.1 g, 0.045 mole) and pyridine (15 ml) is heated at reflux for 3 hours. The solution is cooled and diluted with water. The organic layer is separated and washed successively with 3% sulfuric acid, and water. The solution is dried over sodium sulfate and distilled under vacuum to yield cis-2-nonenyl acetate, b.p. 58° - 62°C/0.1 mm.
Reaction SMILES: [C@H:1]1([NH:9][C:10]([CH:12]([CH:45]([CH3:47])[CH3:46])[CH2:13][CH:14]([OH:44])[CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:16][CH:17]([CH2:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[CH:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH:18]([CH3:20])[CH3:19])=[O:11])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.ClS([N:52]=[C:53]=O)(=O)=O.CN(C)C=O>ClCCl>[C:53]([C:26]1[C:25]2[C:29](=[CH:30][C:22]([CH2:21][CH:17]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[CH:14]([OH:44])[CH2:13][CH:12]([C:10](=[O:11])[NH:9][C@H:1]3[C:3]4([CH2:4][CH2:5][O:6][CH2:7][CH2:8]4)[CH2:2]3)[CH:45]([CH3:47])[CH3:46])=[CH:23][CH:24]=2)[N:28]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:27]=1)#[N:52]
Reactant: COCCCn1ccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCn1cc(C#N)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1 mmol of tert-butyl (4-((R)-(6-oxaspiro[2.5]-oct-1-yl)carbamoyl)-2-hydroxy-1-(2-[1-(3-methoxypropyl)-1H-indol-6-ylmethyl]-3-methylbutyl)-5-methylhexyl)carbamate in 15 ml of dichloromethane is mixed with 1.5 mmol of chlorosulphonyl isocyanate and stirred at room temperature for 16 hours. 2 ml of N,N-dimethylformamide are added, and the reaction mixture is again stirred for 2 hours. It is quenched with water, and the suspension is vigorously stirred for 10 minutes. It is poured into 1M sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:38][CH2:39][Cl:40]>O>[Cl:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 62.1 %

Procedure:
To a mixture of 0.371 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 1.63 g (5 mmole) of cesium carbonate and 3 mL of dimethylformamide was added 0.249 mL (3 mmole) of 1-bromo-2-chloro-ethane. The mixture was heated at 100 degrees for 30 minutes. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration and then air dried. The solid was triturated with acetonitrile to give 0.269 g of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCSc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1ccncc1
Temperature: 90 °C
Yield: 2.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(2-chloroethylthio)pyridine hydrochloride (252 mg, 1.2 mmol) and potassium carbonate (454 mg, 3.3 mmol) in NMP (30 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 75/25) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline (13 mg, 3%). m.p. 182-186° C. 1H NMR Spectrum: (DMSOd6) 3.58(t, 2H); 3.90(s, 3H); 4.40(t, 2H); 7.20(s, 1H); 7.32(d, 1H); 7.40(d, 2H); 7.50-7.60(m, 2H); 7.80(s, 1H); 8.32(s, 1H); 8.38(d, 2H); 9.57(s, 1H) MS-ESI: 457 [MH]+
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reaction time: 7 h

Procedure:
Dimethylformamide (0.6 ml) is added to a mixture of 2,3,4,5-tetrafluorobenzoic acid (100 g) and thionyl chloride (135 ml), and the mixture is heated under reflux with stirring for 7 hours. The reaction mixture is condensed under vacuum to yield crude 2,3,4,5-tetrafluorobenzoyl chloride as a pale yellow oily residue (110.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:41]=[C:40]([CH3:52])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:41]=[C:40]([CH3:52])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(COC4CCCCO4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (320 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (550 mg, 82%).