Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C=C(OC(=O)C(C)(C)C)C=CC=2C1)C.N12CCC(COC3C=CC(C=O)=CC=3)(CC1)CC2.[N:47]12[CH2:54][CH2:53][C:50]([CH2:55][O:56][C:57]3[CH:91]=[CH:90][C:60]([CH2:61][CH2:62][CH2:63][NH:64][C:65]4[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:66]=4[CH:73]4[CH2:82][CH2:81][C:80]5[CH:79]=[C:78]([O:83]C(=O)C(C)(C)C)[CH:77]=[CH:76][C:75]=5[CH2:74]4)=[CH:59][CH:58]=3)([CH2:51][CH2:52]1)[CH2:49][CH2:48]2>>[N:47]12[CH2:54][CH2:53][C:50]([CH2:55][O:56][C:57]3[CH:58]=[CH:59][C:60]([CH2:61][CH2:62][CH2:63][NH:64][C:65]4[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:66]=4[CH:73]4[CH2:82][CH2:81][C:80]5[CH:79]=[C:78]([OH:83])[CH:77]=[CH:76][C:75]=5[CH2:74]4)=[CH:90][CH:91]=3)([CH2:51][CH2:52]1)[CH2:49][CH2:48]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC34CCN(CC3)CC4)cc2)c1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: O=Cc1ccc(OCC23CCN(CC2)CC3)cc1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC34CCN(CC3)CC4)cc2)c1
Yield: 69.6 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-(1-azabicyclo[2. 2.2]oct-4-ylmethoxy)benzaldehyde according to an analogous synthetic method to Example 212, pivalic acid 6-{2-{[4-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)benzyl]ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) was used according to an analogous synthetic method to Example 217 to provide the title compound (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[CH2:25][CH2:26][N:21]([C:18]2[C:17]([CH3:27])=[CH:16][C:15]([CH:12]3[CH2:13][CH2:14]3)=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Yield: 103.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 2-bromo-4-chlorobenzoic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.923 g) described in Preparation Example 96, the title compound (1.91 g) was obtained.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[CH2:22]([N:24](CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.C(Cl)CCl>[NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:24][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)O)c(Nc2ccccc2)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1ccc(OC)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-anilino-4-methoxybenzoic acid (220 mg), methylamine hydrochloride (100 mg), triethylamine (0.31 mL), EDC (260 mg), and HOBt (210 mg) were combined in 4 mL DMF and stirred overnight at room temp. The reaction was diluted with EtOAc and washed with 10% citric acid (1×), water, and 10% sodium bicarbonate, then dried (Na2SO4) concentrated to give 0.23 g of 2-anilino-4-methoxy-N-methylbenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[O:35]1[CH2:39][CH2:38]CC1.C(=O)([O-])[O-].[K+].[K+].[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl>[C:46]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[C:8]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:39](=[O:35])[CH3:38])=[CH:31][CH:32]=3)[S:7][C:6]=2[CH:34]=1)(=[O:48])[CH3:47]
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(-c2sc3cc(OC(C)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Two g. of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene was dissolved in 30 ml. of tetrahydrofuran, and 3.5 g. of potassium carbonate was added. The vessel was blanketed with nitrogen and 0.9 g. of acetic anhydride was added. The mixture was stirred at ambient temperature for 2 hours, and then under reflux for 2 hours more. The mixture was then cooled, and to it was added 200 ml. of chloroform. The mixture was washed with 100 ml. of aqueous sodium chloride solution, and the organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under vacuum at 40° C. A white foam was obtained, which was determined to be the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([OH:56])(=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CCCCCC>[C:37]([O-:56])(=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].[C:37]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Reaction time: 2 h

Procedure:
A mixture of 15 g of phytol, 11 g of dicyclohexylcarbodiimide and 0.1 g of cuprous chloride was stirred at 90°-100° C. for two hours under nitrogen, to which 16 g of oleic acid was added, followed by further two hours' stirring at 90°-100° C. After cooling, the reaction mixture was added with 100 ml of n-hexane, freed from any insoluble matters through filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to yield 12.6 g of isophytyl oleate from the first eluting fraction and 5.9 g of phytyl oleate from the later eluting fraction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH2:18][NH:17][CH2:16][CH2:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:26][C:25]1[C:20]([N:17]2[CH2:16][CH2:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:10]=3[CH2:18]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccnc1Cl
Reactant: Fc1ccc(Nc2ncnc3c2CNCC3)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.47 g, 1.92 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (420 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (200 mg, 30%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:10][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([CH3:40])[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C.O>[C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=3[C:15]([NH:39][S:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:40])(=[O:37])=[O:38])=[O:16])=[CH:10][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(Nc2cc(-c3ccccc3)nn2-c2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2cc(-c3ccccc3)nn2-c2ccccc2)c(C(=O)NS(=O)(=O)c2ccccc2C)c1
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of 2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid (Example 29) (100 mg, 0.26 mmol) in dichloromethane (3 mL) were added o-toluenesulfonamide (53.3 mg, 0.31 mmol), EDCI (99.47 mg, 0.52 mmol), DMAP (63.40 mg, 0.52 mmol), and triethylamine (0.127 mL, 0.91 mmol). The reaction mixture was stirred for 2 h, and then diluted with dichloromethane (10 mL) and water (20 mL). The organic phase was separated and then washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 90% EtOAc/hexane, to afford the product (13.9 mg, 10.0%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.74 (s, 3H) 6.67 (s, 1H), 7.03 (dd, 2H), 7.26-7.60 (m, 14H), 7.84 (dd, 2H), 7.94 (d, 1H). ES-MS m/z 539.1 (MH+); HPLC RT (min) 3.71.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[C:5](SC)=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>[Ni].C(O)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[CH:5]=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: CSc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(N)=O)ccc1C
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reaction time: 12 h
Yield: 56 %

Procedure:
A mixture of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide (0.15 g, 0.00033 mol from step 5), and Raney nickel (0.8 mL, 50% slurry in water) in ethanol (15.0 mL) was refluxed under argon atmosphere. After 12 h, added an additional 0.4 mL of Raney nickel and continued refluxing for another 4 h. The reaction mixture was cooled and the supernatant was decanted off. The catalyst was washed with ethanol, the combined ethanol washings and the supernatant were concentrated under reduced pressure and the resulting residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=406 were combined and concentrated to a small volume (˜20 mL), cooled added 5% sod. bicarbonate (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to dryness to afford the title compound (0.075 g,) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.31 (s, 1H ), 7.94 (dd, 1H. J=2.0 Hz & 8.0 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.53 (m, 1H), 7.02 (m, 2H), 5.59 (m, 2H), and 2.19 (s, 3H); ES-HRMS m/z 406.0774 (M+H calcd for C19H15N3O3F2Cl requires 406.0765); 19F NMR (CD3OD/400 MHz) −111.62 (m) and −115.94 (m).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1(S([Cl:28])(=O)=O)C=CC=CC=1>C(OCC)C.CCOC(C)=O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:28])=[CH:12][N:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1nccs1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ncc(Cl)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of (tert-butyl)(1,3-thiazol-2-ylsulfonyl)amine (0.15 g, 0.7 mmol) in ethyl ether (3 mL) at −78° C. was added a 1.6M solution of n-butyllithium (0.875 mL, 1.4 mmol) in hexanes via syringe under argon: The reaction mixture was stirred at −78° C. for 1 hr, then neat benzenesulfonyl chloride (90 μL, 0.7 mmol) was added. The resulting suspension was stirred at room temp for 2 hr. The reaction was diluted with EtOAc, washed with water and brine, dried, concentrated in vacuo and chromatographed (15% EtOAc/hexane) to give pure desired compound (58 mg, 33%). ES-MS (M+Na)+=277, 279 (Cl), (M−tBu+H)+=199, 201 (Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](Cl)=[O:51]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:50](=[O:51])[C:49]4[CH:53]=[CH:54][CH:55]=[CH:56][C:48]=4[F:47])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM (10 mL) at 0° C. was added DIPEA (0.199 mL, 1.137 mmol) and 2-fluorobenzoyl chloride (135 mg, 0.853 mmol) and the suspension was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was collected, dried and concentrated. The residue was purified using Biotage (eluent EtOAc, 25 g Silicycle HR column) to provide the title compound 356 (400 mg, 0.616 mmol, quantitative yield) as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=O)([CH3:36])[CH3:35]>C1COCC1>[CH:34]([C:37]1[C:44]([O:3][CH3:2])=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=[CH2:24])([CH3:36])[CH3:35]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1c(C(C)C)cc(Br)c(OC)c1C(C)C
Temperature: 0 °C

Procedure:
Methoxymethyl triphenylphosphonium chloride (18.68 g, 54.5 mmol) was suspended in 200 mL of THF at −78° C. Lithium hexamethyldisilazide (1.0 M in THF, 50 mL) was added dropwise. The resulting mixture was warmed up to 0° C. with stirring. After cooling the solution to −78° C., 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g, 42.7 mmol) in 20 mL of THF was added dropwise. The mixture was slowly warmed up to room temperature and continually stirred overnight. After regular work up, the crude product was distilled at 165° C. under vacuum to afford 2,6-diisopropyl-4-bromo-3-methoxystyrene (10 g). This product was dissolved in 20 mL of dioxane and 100 mL of 18% HCl solution and refluxed at 100° C. for 6 h. After regular work up, the crude product was distilled at 160° C. under vacuum to afford 2,6-diisopropyl-4-bromophenylacetaldehyde (7.5 g).
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C@H:24]([CH2:38][OH:39])[CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:34][CH2:33]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[C:20](=[O:40])[C@@H:19]2[CH3:41])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12]>C(#N)C.[Ag-]=O>[Cl:3][C:4]1[CH:5]=[C:6]([N:15]([CH3:2])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C@H:24]([CH2:38][OH:39])[CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:33][CH2:34]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[C:20](=[O:40])[C@@H:19]2[CH3:41])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:13])([F:14])[F:12]
Reactant: CI
Reactant: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Agent: O=[Ag-]
Solvent: CC#N
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)N(C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A solution of 0.02 ml (0.345 mmol) of iodomethane and 0.040 g (0.069 mmol) (S)-4-[(S)-4-(S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3-chloro-4-trifluoromethoxy-phenyl)-amide (example 55) in 1.5 ml of acetonitrile was cooled (0° C.) and treated with 0.023 g (0.100 mmol) of silver(I) oxide. The reaction mixture was stirred at RT for 1 day, treated again with 0.02 ml (0.345 mmol) of iodomethane and stirred for 3 days. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.040 g (88%) of the titled compound as off-white foam. MS: 591.22 (MH+, Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[N:7]=2)=[CH:9]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1nccc(-c2ccsc2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNc2nccc(-c3ccsc3)n2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
To a solution of 14 (680 mg, 3.46 mmol) and methyl 4-(aminomethyl)benzoate (686 mg, 4.51 mmol) in dry 1,4-dioxane (10 mL) was added DIPEA (1.50 mL, 8.65 mmol) and the mixture was heated for 48 h at 130° C. in a sealed tube. Solvents were removed under vacuum and the residue was triturated with a mixture of EtOAc/Et2O, to form a solid, which was collected by filtration and dried. This material was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 30/70) to afford the title compound 15 (540 mg, 1.66 mmol, 48% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.29-8.23 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.43 (m, 2H), 7.03 (d, J=5.2 Hz, 1H), 4.60 (d, J=6.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(C)cccc2Cl)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Yield: 46.1 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-6-methylbenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (2.0 g), TFA (5 mL) and DCM (30 mL) to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.31 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 7.40 (s, 1H), 7.49 (s, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 12.54 (s, 1H); MS (m/z): 373.95 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>C(#N)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Reactant: OCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.34 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.34 g.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:14][S:15]([O:13][CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]1)(=[O:17])=[O:16]
Reactant: CCCCCC1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCC1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
8.0 g of 4-n-pentylcyclohexylmethanol was dissolved in a mixture solvent of 8 ml of pyridine and 8 ml of toluene. To the solution, 6.0 g of methanesulfonyl chloride was added dropwise below 10° C., followed by stirring overnight at room temperature. After the reaction, the reaction mixture was poured into cold water and subjected to extraction with toluene, followed by washing successively with 5%-hydrochloric acid aqueous solution and water and drying with anhydrous magnesium sulfate. The resultant organic layer was subjected to filtration, followed by distilling-off of the solvent to obtain 11.3 g of 4-n-pentylcyclohexylmethyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][CH:30]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Cl)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H18ClF3N4O3 (m/e) 454, obsd 455 (M+H).