Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28]([NH2:30])[CH3:29]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:30][C@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH3:29])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Reactant: C[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1)c1ccccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 62.8 %

Procedure:
A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 92 mg of (S)-1-(2-fluorophenyl)ethylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (170 mg) with a molecular weight of 469.4 g/mol (C20H22BrFN2O3S); MS (ESI): m/e=469 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(OCC)C>[NH+:1]1([O-:18])[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: [O-][NH+]1C=Cc2cccnc21
Yield: 125 %

Procedure:
To 1H-pyrrolo[2,3-b]pyridine (94, 3.0 g, 25.3 mmol) dissolved in 175 ml, of diethyl ether was added m-CPBA (1.5 equiv) in portions over 30 minutes with vigorous stirring. The solution turned yellow, and precipitates formed. After two hours the solid was collected, washed with 2×50 mL of ether, and recrystallized from acetone:ether. Yield was approximately 125% due to contaminating acid. This crude material was carried through to the next step.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:3][C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=4)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=3[N:6]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(Br)cc3)sc2c1-c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (200 mg, 0.403 mmol), 4-bromophenylboronic acid (113 mg, 0.564 mmol), tetrakis(triphenylphosphine)palladium(0) (69.8 mg, 0.060 mmol), and K2CO3 (167 mg, 1.208 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (4 mL) and degassed water (1 mL). The reaction mixture was stirred at 75° C. for 5 h, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C28H28BrClNO3S (M+H+): 572.1 and 573.9; Found: 574.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: CCCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 42.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-butoxybenzaldehyde 1.66 g were dissolved in methanol 60 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 2.5 hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: CCC(CC)(NC(=O)c1ccc(C)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and 2-amino-2-ethyl-N-methyl-butyramide as starting materials, MS (LC/MS): 374.2 [M+H]+.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=1)C.[CH2:20](N)[CH2:21][NH2:22]>CO>[ClH:1].[NH:22]1[CH2:21][CH2:20][N:19]=[C:5]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=N)COc1cccc(NS(C)(=O)=O)c1
Reactant: NCCN
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Yield: 20.2 %

Procedure:
2-(3-Methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride (0.8 g) was suspended in 12 ml of absolute methanol (MeOH) and treated with 0.16 g of ethylene diamine. After 8 hours at room temperature the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol:dichloromethane:ammonium hydroxide (16:84:0.1). Conversion to the hydrochloride salt by addition of 1.0M hydrogen chloride in ether gave 0.16 g of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy) phenyl] methanesulfonamide hydrochloride, mp 183-187° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([CH:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH3:18])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:35](Cl)(Cl)=[O:36]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:35](=[O:36])[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:17]([CH3:18])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2C(C)Nc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Cl)nc32)cc1

Procedure:
A solution of (±)-{2-chloro-5-[1-(4-methoxy-phenylamino)-ethyl]-pyrimidin-4-yl}-(4-methoxy-phenyl)-amine (49.4 mg; 0.13 mmol) (from Example 1f supra) in dichloromethane (1.5 mL) was cooled in an ice-water bath. To this solution was added triethylamine (0.18 mL; 1.29 mmol) (Aldrich), followed by phosgene solution (1.89 M, 0.34 mL; 0.64 mmol) (Fluka). After two hours in the cold, the reaction was diluted with additional dichloromethane and washed sequentially with water, dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate, and brine. The organic layer was then dried over anhydrous sodium sulfate and concentrated. Residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes as solvent) to give (±)-7-chloro-1,3-bis-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 42.6 mg; 79.2%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: C[C@H](O)C(=O)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:46]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:49]2[CH2:48][CH2:47][N:46]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 mL) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33ClN2O4, 436.2129; found (ESI_FT), 437.21996.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:27]([O:33][CH2:34][O:14][C:13](=[O:15])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.3 g (0.06 mol) of 4-(4'-chlorobenzyl)-phenoxy acetic acid in 50 ml of dimethylformamide are added 6.0 g (0.06 mol) of triethylamine, whereafter the mixture is stirred for 30 minutes at room temperature and, after adding 9.0 (0.06 mol) of chloromethyl pivalate, is heated for 6 hours in an oil bath at 85°-90° C. The residue which is obtained by concentration by evaporation at reduced pressure in a Buchi rotary evaporator is washed with water and extracted with ether. The ethereal solution is once again washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation in the Buchi rotary evaporator, an oil being obtained which quickly solidifies. By recrystallisation from ether/n-hexane, 9.5 g of product are obtained in the form of white crystals with the melting point 54°-55° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:4]4[CH2:3][CH2:2][S:1][CH2:6][C:5]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: ON=C1CCSCC1
Product: Clc1ccc(N2CCN(CCCc3onc4c3CSCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using tetrahydro-4H-thiopyran-4-one oxime and ethyl 4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-thiopyrano[4,3-c]isoxazole is obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(CCCCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)c2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-phenylsulfinylpentyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylsulfinylpentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:3]=1
Reactant: Cc1ccc2c(I)n[nH]c2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(I)nn(CCN(C)C)c2c1
Temperature: 25 °C
Yield: 151.9 %

Procedure:
A mixture of 3-iodo-6-methyl-1H-indazole (516 mg, 2 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (346 mg, 2.4 mmol) and potassium carbonate (828 mg, 6 mmol) in 20 mL of DMF was heated to 80 degree overnight. After cooling to room temperature, water (50 mL) was added, product extracted with dichloromethane (3×50 mL), combined organics were dried with sodium sulfate, and concentrated to give 2-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylethanamine (1 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.33 (d, 1H, J=8.1 Hz), 7.15 (s, 1H), 7.03 (d, 1H, J=0.6 Hz), 4.47 (t, 2H, J=7.2 Hz), 2.81 (t, 2H, J=7.2 Hz), 2.51 (s, 3H), 2.34 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:4]([CH3:18])[C:3]=1[CH3:19].CO.[BH4-].[Na+].Cl>O1CCCC1>[OH:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[C:4]([CH3:18])=[C:3]([CH3:19])[C:2]([OH:1])=[C:7]([CH3:8])[C:6]=2[CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(C)c(-c2cccc(C=O)c2)c(C)c(C)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of 4′-hydroxy-2′,3′,5′,6′-tetramethylbiphenyl-3-carbaldehyde (2.03 g, 8.00 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.336 g, 8.00 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (1.90 g, yield 93%) as colorless crystals. melting point 152-153° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8]2([CH3:16])[CH3:15].[CH3:17]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH3:17])[C:8]2([CH3:16])[CH3:15]
Reactant: CI
Reactant: COc1ccc2c(c1)C(C)(C)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C)(C)N(C)C2=O
Reaction time: 0.5 h

Procedure:
With cooling with ice, 96 mg of 60% sodium hydride was added to 8.0 mL of a DMF solution of 382 mg of 5-methoxy-3,3-dimethylisoindolin-1-one, and stirred for 30 minutes with cooling with ice. 0.19 mL of methyl iodide was added to it, and stirred at room temperature for 7 hours. The solvent was evaporated away under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 381 mg of the entitled compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1cccc(-c2nc(CBr)sc2Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a solution of 5-Bromo-2-bromomethyl-4-(3-methoxy-phenyl)-thiazole (0.80 g, 2.20 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.38 g, 2.20 mmol) and potassium carbonate (1.06 g, 7.70 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.50 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C

Procedure:
2-Methylbenzothiazole (22 g) in conc. sulfuric acid (80 ml) was cooled to −5° C. A mixture of conc. sulfuric acid (12 ml) in conc. nitric acid (20 ml) was added so as to maintain the temperature below 5° C. (ca. 1.5 hours). After this time the mixture was allowed to warm to room temperature and the solution poured onto ice to give a yellow precipitate. The solid was removed by filtration and recrystallised from ethanol. After filtration the solid was washed with ethanol and dried in a vacuum oven to give 18 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42](O)=[O:43])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:43]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccn2)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccn3)sc2N)c1N1CC[C@H](N)[C@@H](F)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)thiazole-4-carboxylic acid gave 298 as a pale yellow solid (418 mg, 74% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.78-7.73 (m, 2H), 7.28-7.23 (m, 1H), 6.26 (s, 2H), 4.51 (dtd, J=48.0, 8.8, 3.8 Hz, 1H), 3.73 (s, 3H), 3.37-3.20 (m, 5H), 2.35-2.21 (m, 1H), 2.18-2.04 (m, 1H), 2.02-1.92 (m, 1H), 1.79-1.66 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 431 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([OH:30])=O)[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:30])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4nncn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and N-methylpiperazine were reacted in the general amide coupling procedure to give 374. NMR: (CDCl3): 2.37 (3H, s, Me), 2.37-2.51 (4H, m), 3.13-3.17 (2H, m), 3.51-3.78 (4H, m), 4.32-4.35 (2H, m), 6.98 (1H, s, Ar), 7.05 (1H, d, J 8.3, Ar), 7.12-7.17 (2H, m, Ar), 7.24-7.27 (1H, m, Ar), 7.42-7.48 (1H, m, Ar), 7.61-7.62 (1H, m, Ar) and 8.24 (1H, s, Ar). MS: (ESI+) MH+=508.22
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2[C:13](=[O:15])[O:12][CH2:11][C:10]3[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([O:20][CH3:21])[C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26].[CH3:29][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:28][C:23]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:9]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:10]=3[CH2:11][O:12][C:13](=[O:15])[C:14]=2[C:3]=1[O:2][CH3:1])([CH3:29])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C)cc2c1Oc1ccc(C(C)(O)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4,11-dimethoxy-9-methyl-3-(3-methylbutan-1-onyl)-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 5 ml of absolute tetrahydrofuran under argon and 0.2 ml (0.6 mmol) of a 3M methylmagnesium bromide solution in diethyl ether are added at room temperature. After 4 h, the reaction is discontinued by addition of 0.2 ml of ammonium chloride solution. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. After drying the organic phase over magnesium sulphate, it is concentrated and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 10:1.