Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:24]2[CH:28]=[N:27][C:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([CH2:39][NH2:40])[CH:36]=[CH:35][N:34]=3)=[N:25]2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:40][CH2:39][C:37]2[CH:36]=[CH:35][N:34]=[C:33]([O:32][CH2:31][CH2:30][CH2:29][C:26]3[N:27]=[CH:28][NH:24][N:25]=3)[CH:38]=2)=[O:14])[NH:3]1
Reactant: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NCc1ccnc(OCCCc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (25.0 mg, 0.11 mmol), 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methanamine obtained in Reference Example 28 (28.0 mg, 0.069 mmol) and diisopropylethylamine (159 mg, 1.20 mmol) in ethanol (3 mL) was stirred at 80° C. for 15 hr. After cooling the mixture to room temperature, the resulting solid was collected by filtration, and washed with ethanol. 4N Hydrochloric acid and ethyl acetate were added to the crude crystals, and the mixture was stirred at room temperature for 2 hr. Water was added to the mixture, and the aqueous layer was weakly acidified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (28.0 mg, 60%).
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]([CH3:12])=[N:11][N:7]2[C:6]([C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:40])[C:23]3[CH:28]=[C:27]([N:29]=[N:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH:26]=[CH:25][C:24]=3[OH:39])[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:5]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([NH:21][C:22](=[O:40])[C:23]2[CH:28]=[C:27]([N:29]=[N:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[CH:26]=[CH:25][C:24]=2[OH:39])=[CH:14][C:13]=1[C:6]1[N:7]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[NH:4][N:5]=1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc(OC)c(-c4nn(C(C)=O)c5cc(C)nn45)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc(OC)c(-c4n[nH]c5cc(C)nn45)c3)c2)cc1
Reaction time: 0.25 h

Procedure:
N-[3-(1-Acetyl-6-methyl-1H-pyrazolo[3,2-c]-s-triazol-3-yl)-4-methoxyphenyl]-2-hydroxy-5-(4-methoxyphenylazo)benzamide (1.4 g) was dissolved in methanol (100 ml) and a solution of sodium hydroxide (1.0 g) in water (30 ml) added. After stirring for 15 minutes the solution was acidified with glacial acetic acid when a gelatinous precipitate of the product appeared. This was removed by filtration, washed with water and crystallized in aqueous pyridine (850 mg; 66%), m.p. 295°-6°, λmax (methanol) = 350 nm.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)[Cl:8].[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=O)[CH2:17][CH2:18][O:19]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:8])=[C:17]([CH:3]=[O:4])[CH2:18][O:19]2)=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=C1CCOc2cc(Br)ccc21
Solvent: ClC(Cl)Cl
Product: O=CC1=C(Cl)c2ccc(Br)cc2OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Anhydrous dimethylformamide (8.18 ml, 106 mmol) was taken in a two-necked round bottomed flask fitted with a dropping funnel. POCl3 (7.23 ml, 78 mmol) was added to it by keeping the flask in an ice bath and after the completion of addition, the ice bath was removed and the mixture was stirred at RT for 1 hr. 7-bromochroman-4-one (16 g, 71 mmol) was dissolved in 200 ml of chloroform and was slowly added to the flask kept on an ice bath, and after completion of the addition, the ice bath was removed and the reaction mixture was stirred overnight at 60° C. The reaction was brought to RT and ice cold water was added to it and the compound was extracted with chloroform. The organic layer was washed with 10% NaHCO3 solution and dried over Na2SO4, filtered and concentrated to obtain the crude title compound (15.1 g, 78%) which was sufficiently pure enough for the next step. m/z 273.9 (M+)
Reaction SMILES: O1CCCC1.[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: C#Cc1cccnc1N
Reactant: Cc1ccc(Oc2ccc(CC(Cl)=NO)s2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Cc3cc(-c4cccnc4N)on3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 1.6 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (5-p-tolyloxy-thiophen-2-yl)-acetohydroximoyl chloride (191 mg, 0.678 mmol) described in Manufacturing Example 48-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.03 mg, 1.65%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CBr
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CNc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydrous THF at 0° C. was added 2-bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 mL of THF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0° C. 3-bromo-2-methylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0° C. for 3 h then neutralized with water (5 mL). The mixture was extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 200 mg (32%) of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (structure 55A of Scheme XLVII, where R1 =methyl, R2 =H). Data for 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline: 1H NMR (400 MHz, CDCl3) 7.55 (d, J=8.5, 1H), 7.40 (dd, J=8.5, 2.8, 1H), 7.39 (d, J=2.8, 1H), 4.96 (s, 2H), 4.95 (bs, 1H), 3.82 (d, J=5.9, 2H), 1.81 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21]([O:23]C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:25]>C1COCC1.[OH-].[NH4+]>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21](=[O:23])[NH2:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Temperature: 35 °C

Procedure:
A solution of 9-[(cyclopentyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (110 mg, 0.34 mmol) in 3 mL of THF and 20 mL of concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (20 h). The THF was evaporated, and the aqueous layer was filtered. The resultant solid was triturated with ether to afford 50 mg (0.162; 48%) of the title compound as a greenish-white solid. IR (KBr, cm−1) 3416, 3199, 3126, 1630, 1599. 1442, 1262, 778. FAB HRMS m/e, Calcd for C20H21N2O2: 309.1603. Found: 309.1607 (M+1).’
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH3:19])[C@@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20]I>CN(C=O)C.O>[CH3:20][O:12][C:11](=[O:13])[C@H:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: CI
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](OS(C)(=O)=O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
Jones reagent was prepared by mixing chromium (VI) oxide (2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10 min. The solution was used directly, and was added dropwise to a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g, 4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was added and the mixture was concentrated. Water was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give the crude acid. To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO3 (1.44 g, 14.4 mmol) and MeI (0.90 mL, 14.4 mmol). After 12 h, the mixture was diluted with water and extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography to give 1.13 g (69% over 2 steps) of the desired product. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.3, 1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7, 1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:4](=[O:6])[C:3]([O:2][CH3:1])([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH3:7])=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C)(C(=O)O)c1cccc2ccccc12
Product: COC(C)(C(=O)NCc1ccc(C#N)cc1)c1cccc2ccccc12

Procedure:
2-Methoxy-2-(1-naphtyl)propionic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-naphthalen-1-yl-propionamide. Colorless foam. MS 345.2 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19](SCCO)=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].O[O:35][S:36]([O-:38])=O.[K+].C([O-])(O)=O.[Na+].C1C[O:48][CH2:47][CH2:46]1>CO.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:36]([CH2:46][CH2:47][OH:48])(=[O:38])=[O:35])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccc(SCCO)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)CCO)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reaction time: 1.5 h

Procedure:
To 7-chloro-3-[4-(2-hydroxy-ethylsulfanyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (100 mg) in a mixture of THF and MeOH (1:5, 12 mL) was added a solution of OXONE™ (294 mg) in water (3 mL) at 0° C. The reaction mixture was stirred for 1.5 h, and NaHCO3 (sat aq, 20 mL) added. The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a yellow-brown oil. The crude residue was purified by flash chromatography (EtOAc/hexane) to give 7-chloro-3-[4-(2-hydroxyethane-sulfonyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (23.6 mg) as an off-white powder. MS=512 [M+H]+; MP=172.2-173.5° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (420 mg, 1.48 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (742 mg, 2.78 mmol) in acetonitrile (8 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to yield the product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[N+:19]([CH:10]1[CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]1([CH3:13])[CH3:12])([O-:21])=[O:20]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC([N+](=O)[O-])C(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0° C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL of ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo to provide 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].[CH3:25][C:26]1[N:27]=[C:28]([NH:31][C:32]2[CH:39]=[C:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][CH:42]=3)[C:35]([CH:36]=O)=[CH:34][N:33]=2)[S:29][CH:30]=1.[C:51]([O:54][CH2:55]C)(=[O:53])[CH3:52]>C1COCC1>[CH3:25][C:26]1[N:27]=[C:28]([NH:31][C:32]2[N:33]=[CH:34][C:35](/[CH:36]=[CH:5]\[C:1]([O:3][CH3:4])=[O:2])=[C:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][CH:42]=3)[CH:39]=2)[S:29][CH:30]=1.[CH3:25][C:26]1[N:27]=[C:28]([NH:31][C:32]2[N:33]=[CH:34][C:35](/[CH:36]=[CH:52]/[C:51]([O:54][CH3:55])=[O:53])=[C:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][CH:42]=3)[CH:39]=2)[S:29][CH:30]=1
Reactant: CCOC(C)=O
Reactant: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C=O)cn2)n1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Product: COC(=O)/C=C\c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Reaction time: 2 h
Yield: 14 %
Yield: 43 %

Procedure:
Carbomethoxymethylene triphenylphosphorane (0.517 g, 1.55 mmol) was added to a solution of 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinaldehyde (0.430 g, 1.19 mmol) in THF (5 mL). The reaction mixture was stirred for 2 hours and then concentrated, and the residue was purified via MPLC (Biotage), eluting with 1:1 hexane:ethyl acetate to provide (Z)-methyl 3-(6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)acrylate (0.072 g, 14% yield) and (E)-methyl 3-(6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)acrylate (0.216 g, 43% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:25])=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51]>CN(C)C1C=CN=CC=1.ClCCl>[C:50]([NH:54][C:30]([C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:11]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:36])([CH3:1])[CH3:37])=[CH:15][CH:14]=3)=[O:25])[CH:35]=[CH:34][CH:33]=1)=[O:31])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cccc(C(=O)O)c1)n2Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cccc(C(=O)NC(C)(C)C)c1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 mg (0.04 mmol) of the compound from Example 64, 11.5 mg (0.06 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 2.5 mg (0.02 mmol) of 4-dimethylaminopyridine are initially charged in 1 ml of dichloromethane. 3.5 mg (0.05 mmol) of tert-butylamine are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. Purification is carried out by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][N:38]=1.CCOCC>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:38]3[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]3=[N:36][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1F
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3c(F)cccn3c2-c2ccnc(Cl)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (4.0 g, 10.34 mmol) in DCM (103 mL) at rt under N2 was added NBS (1.84 g, 10.34 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (103 mL) and 2-amino-3-fluoropyridine (3.47 g, 31.0 mmol) was added. The reaction was stirred under N2, heated to 80° C., and stirred for approximately 40 h, then cooled to rt. The reaction was diluted with EtOAc (200 mL) and half-saturated aqueous NaHCO3 (150 mL). The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM and ether was added until a precipitate formed. The slurry was filtered, washing the solids with cold ether. The solids were dried under vacuum to give the title compound of step A (1.58 g, 3.29 mmol, 32%) as a white solid. MS (ESI): 480 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole as light yellow solid, MS: 429 (M, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[CH:7][C:6]=1[F:13])[CH3:2].C(N(CC)CC)C.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:31]2[CH2:32][CH2:33][CH:29]([NH:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:34])[CH2:30]2)=[CH:7][C:6]=1[F:13])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1F
Reaction time: 45 h

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98–100° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:32][C:13]([CH3:12])([CH3:33])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: CCCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CCCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl 2,2-dimethylpropanoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 38 (90 mg, 12% yield) as a white powder after work-up and mass-guided preparative HPLC purification, 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.99 (m, 5H), 1.12-1.38 (br. m, 14H), 1.69-1.74 (m, 4H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.2 Hz, 1H), 2.78-2.91 (m, 2H), 6.61 (t, J 5.6 Hz, 1H), 7.47 (t, J=6.0 Hz, 1H), 12.04 (s, 1H), MS (ESI) m/z 380.22 (M+Na)+; 356.18 (M−H)−.