Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][OH:23])[N:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[N:9]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCCO)n2)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCc2nc(NN=Cc3cccc(C)c3)cc(N3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
S5; 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propan-1-ol (355 mg, 1 mmol) was dissolved in acetonitrile (4 mL). To the mixture was added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction was stirred at 60° C. for 16 hours. The reaction was then cooled to 4° C., and the precipitate was filtered, washed with acetonitrile (1 mL) and dried to give Compound 1, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23]Br)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[CH:18]([O:27][C:28](=[O:30])[CH3:29])[CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1>CN1CCCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[CH:18]([O:27][C:28](=[O:30])[CH3:29])[CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Temperature: 25 °C
Yield: 7263.6 %

Procedure:
A solution of 0.45 g (0.88 mmol) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 0.24 g (3.5 mmol) of pyrazole in 15 mL of N-methyl pyrrolidine was heated to 100° C. After 2 hours the reaction was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution, hexane-16% ethyl acetate/hexane) to afford 32 g (73%) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazol-1-ylmethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+=500).
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:23]2=[C:24]([CH:27]=1)[O:25][CH2:26][C:20]1[CH:19]=[C:18]([CH2:17][N:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[N:8]=[C:7]3[N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:37]=[CH:36][C:21]=1/[C:22]/2=[C:32](/[CH3:35])\[C:33]#[N:34]
Reactant: c1ccc2[nH]c(N3CCCCC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(N4CCCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 76.8 %

Procedure:
Using commercially available 2-(piperidin-1-yl)-1H-benzo[d]imidazole (67 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (125 mg, 78%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.S(=O)(=O)(O)O.O.[C:17](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:17])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C([O-])O
Reactant: Nc1nccnc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nccnc1N
Reaction time: 48 h
Yield: 63 %

Procedure:
3-Aminopyrazine-2-carboxylic acid (55.5 g, 0.4 mol) is suspended in 400 mL of methanol, cooled in an ice bath and concentrated sulfuric acid (80 mL) is gradually added with stirring and stirring then continued for 48 hours at room temperature. The resulting dark brown solution is poured into 700 mL of water containing sodium bicarbonate (160 g). The brown crystalline solid which precipitates is collected and dried. The crude product is purified by recrystallization from water to yield the product as yellow needles in 63% yield, melting point 169°-170° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22](=[O:45])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:22]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])=[O:45]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Yield: 98.1 %

Procedure:
To 0.59 g of (1S,4S)-(1-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid tert-butyl ester in 5 mL of dichloromethane under stirring were added 5 mL of trifluoroacetic acid. The reaction was followed by TLC and upon disappearance of the starting material the mixture was evaporated in vacuo. The residue was taken up in ethyl acetate and the organic layer washed with aqueous 1.0N sodium hydroxide, with brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and then placed under mechanical vacuum overnight to provide 0.49 g (94%) of title compound as a light brown foam. The product was used without further purification to give a series of diphenyl-propionamide derived tests compounds.
Reaction SMILES: [C:1]1([C:7]2[N:8]([NH2:22])[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:16]1([C:9]2[N:8]([N:22]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nn1c(-c2ccccc2)c2c(c1-c1ccccc1)CCCC2
Product: CS(=O)(=O)N(n1c(-c2ccccc2)c2c(c1-c1ccccc1)CCCC2)S(C)(=O)=O

Procedure:
1,3-Diphenyl-4,5,6,7-tetrahydro-2H-2-isoindolamine (Example 11) is treated with 2 equivalents of methanesulphonyl chloride.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][C:39]5[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([C:39]5[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4nccn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)c4nccn4C)cc2)CCN3CC(C)C)cc1
Yield: 40 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (355 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and sodium thiosulfate solution was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (246 mg) (Compound 160) as yellow amorphous.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19])C1C=CC=CC=1>[Pd].CO>[CH3:28][N:27]([CH3:29])[C:23]1[CH:22]=[C:21]([NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: CN(C)c1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)ccn1
Reaction time: 8 h

Procedure:
Palladium on carbon (10.4 mg; 10% Pd/C) was added to a solution of (2S,5R)-6-(benzyloxy)-N-[2-(dimethylamino)pyridin-4-yl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (47.8 mg, 0.121 mmol) in methanol (2 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. HPLC analysis showed reaction complete. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([F:22])=[CH:15][C:14]=1[O:23][CH3:24].[F:25][C:26]([F:46])([F:45])[C:27]1[CH:28]=[C:29]([C@H:37]2[O:42][C:41](=[O:43])[NH:40][C@@H:39]([CH3:44])[CH2:38]2)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:46][C:26]([F:25])([F:45])[C:27]1[CH:28]=[C:29]([C@H:37]2[O:42][C:41](=[O:43])[N:40]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=3[C:13]3[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([F:22])=[CH:15][C:14]=3[O:23][CH3:24])[C@@H:39]([CH3:44])[CH2:38]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 13; 61.7 mg; 0.152 mmol) and (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 41.5 mg; 0.127 mmol) in DMF (1 mL) under an atmosphere of N2 was added potassium tert-butoxide (14.2 mg; 0.127 mmol). The reaction stirred at room temperature for 1 h and was quenched with sat. NH4Cl. The reaction was partitioned between EtOAc (15 mL) and sat. NH4Cl (10 mL). The aqueous layer was re-extracted with EtOAc (4×25 mL), and the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=652.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropsiomers): δ 7.87 (s, 2H), 7.79 (s, 1H), 7.65 (s, 1H), 7.62-7.59 (m, 1H), 7.36-7.32 (m, 1H), 7.03 (d, J=10.9 Hz, 1H), 6.70 (d, J=11.9 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 5.10 (d, J=16.3 Hz, 1H), 4.39 (d, J=16 Hz, 1H), 3.78 (s, 3H), 3.45-3.37 (m, 1H), 3.25-3.18 (m, 1H), 2.32-2.22 (m, 1H), 1.91-1.78 (m, 1H), 1.27-1.21 (m, 6H), 1.02 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[CH:7]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)[CH2:48][O:47]1>ClCCl>[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH:57][C:12](=[O:14])[C@@H:11]([N:9]3[CH2:10][C:6]([O:5][C:4]4[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=4[F:23])=[CH:7][C:8]3=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:53]2)[CH2:48][O:47]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 2.20 mmol) in dichloromethane (39 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 mL, 2.40 mmol) and 1-hydroxybenzotriazole (0.31 g, 2.29 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.53 g, 2.68 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.56 g, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C25H30N4O5FCl [M+H]+ 521.1962, observed 521.1963; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.46 (br. s., 1H), 1.51-1.65 (m, 1H), 1.71-1.82 (m, 1H), 3.74 (dd, J=8.5, 5.8 Hz, 1H), 4.01 (dd, J=8.2, 6.3 Hz, 1H), 4.04-4.18 (m, 2H), 4.25 (d, J=18.5 Hz, 1H), 4.35 (dq, J=6.0, 5.8 Hz, 1H), 4.61 (d, J=18.5 Hz, 1H), 4.89 (dd, J=10.9, 4.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.3 Hz, 1H), 7.50-7.60 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:22])=O.N>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=2)[N:10]=[CH:9][C:8]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Temperature: 25 °C

Procedure:
Ethyl 6-ethoxy-4-hydroxy-1,5-naphthyridine-3-carboxylate (3.0 g) was added to phosphorus oxychloride (25 ml), with stirring, at ambient temperature. The mixture was heated at 50° C. for 45 minutes. The mixture was cooled to 10° C. and added to ice/water at less than 5° C. The mixture was then basified with concentrated aqueous ammonia solution SG 0.88 at less than 5° C. The mixture was extracted with dichloromethane to give ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate, m.p. 61°-64° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:29])[C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:16]([C:15]1[CH:14]=[C:13]([CH3:12])[C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Reactant: NC(=O)c1cccc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3c(Cl)cccc3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-3-chloro-benzamide (0.85 g, 5.00 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.23 g, 5.00 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.37 g, 7.50 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol). The reaction mixture was stirred at 140° C. for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added, and the mixture was neutralized, to pH approximately 8 with 2 N aqueous NaOH solution. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and then 5% 7.0 M ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a brown solid. Yield: 0.49 g (25%). MP 216-217° C. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J=7.81 Hz, 1H), 8.01-7.87 (m, 3H), 7.43 (t, J=7.81 Hz, 1H), 3.89 (t, J=5.85 Hz, 2H), 2.81 (t, J=5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.75-1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18]([NH2:21])([CH3:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[N:9]([CH3:22])[N:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:32]1([NH:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:37]([NH:21][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]3[N:9]([CH3:22])[N:8]=[C:7]([CH2:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[CH:11]=3)[CH:13]=2)([CH3:20])[CH3:19])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)NC1CCC1
Reactant: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude amine was dissolved in CH2Cl2 (5 mL) and Et3N (222 μL, 1.6 mmol) and crude cyclobutylsulfamoyl chloride (136 mg, ca. 0.8 mmol) were added and the reaction was stirred at RT for 30 min. The reaction was evaporated under reduced pressure and diluted with MeCN:DMSO (1:1, 2 mL) and filtered. The filtrate was injected on to a reverse phase HPLC system and the title compound was isolated, after basic workup, as a yellow gum (4 mg, 1% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.52-7.48 (2H, m), 7.41 (1H, t, J=8.6 Hz), 7.31-7.23 (3H, m), 6.98 (2H, t, J=8.8 Hz), 6.02 (1H, s), 4.49 (1H, s), 4.10 (1H, d, J=8.4 Hz), 3.96 (2H, s), 3.85 (3H, s), 3.82-3.73 (1H, m), 2.30-2.21 (2H, m), 1.90-1.79 (2H, m), 1.73 (6H, s), 1.72-1.63 (2H, m). MS (ES+) C24H29FN4O2S requires 456: found: 457 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 79.8 %

Procedure:
A solution of [(R)-(8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.6 g, 1.25 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum(IV) oxide (45 mg, 0.198 mmol) and the mixture hydrogenated at 45 psi of hydrogen for 2 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 0–15% ethyl acetate in hexanes afforded 0.48 g (80%) of [(R)-8-(2,6-dichlorophenyl)-6-fluorochroman-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. [α]D25=+9.51° (c 5.3 mg/0.7 mL MeOH); MS (ES) m/z 498.0 ([M+NH4]+).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][CH2:6][C:5]([CH2:10][O:11]CC)([CH2:8][OH:9])[CH2:4][O:3]1.O>CO>[CH2:2]([O:3][CH2:4][C:5]([CH2:8][OH:9])([CH2:10][OH:11])[CH2:6][OH:7])[CH3:1]
Reactant: CCOCC1(CO)COC(C)(C)OC1
Solvent: CO
Solvent: O
Product: CCOCC(CO)(CO)CO
Reaction time: 4 h

Procedure:
A mixture consisting of 2,2-dimethyl-5-ethoxymethyl-5-hydroxymethyl-1,3-dioxane (15.0 g) and Amberlyst "15" (3.0 g) in methanol (500 ml) containing water (10 ml) was refluxed with stirring for 4 hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Ethoxymethyl-2-hydroxymethylpropan-1,3-diol was obtained as a viscous oil (10.5 g) and was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]=[C:11]([N:20]3[CH2:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[CH2:22][CH2:21]3)[CH:10]=2)[CH2:6][O:5][CH2:4]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[O:31]=[S:23]1(=[O:32])[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH2:26][N:20]([C:11]2[CH:10]=[C:9]([NH:8][CH2:7][C:3]3([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[CH2:6][O:5][CH2:4]3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]=2)[CH2:21][CH2:22]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1
Product: CC(=O)NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (prepared in analogy to Example 3-50) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (d, J=7.6 Hz, 1 H), 7.89 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.46 (t, 2 H), 7.32-7.30 (m, 1 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 4.56-4.51 (m, 6 H), 3.67 (d, 4 H), 3.60 (t, J=9.6 Hz, 2 H), 2.43 (s, 3 H), 2.06 (s, 3 H).