Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([O:15][CH2:16][O:17][CH3:18])([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[CH:12])[CH3:7].[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38](=[O:40])[CH3:39])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38]([OH:40])([C:12]#[C:11][CH2:10][CH2:9][C:8]([CH2:13][CH3:14])([O:15][CH2:16][O:17][CH3:18])[CH2:6][CH3:7])[CH3:39])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)C1CCC2C(OC(=O)c3ccccc3)CCCC12C
Reactant: C#CCCC(CC)(CC)OCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)(CCC#CC(C)(O)C1CCC2C(OC(=O)c3ccccc3)CCCC21C)OCOC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
0.32 ml of 1.6M hexane solution of butyl lithium was dropwise added to a solution of 120 mg of 5-ethyl-5-methoxymethoxy-1-heptyne dissolved in 4 ml of tetrahydrofuran, at -78° C. in a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added a solution of 112 mg of 4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl-ethanone dissolved in 3 ml of tetrahydrofuran. The reaction mixture was warmed to 0° C. and mixed with an aqueous ammonium chloride solution. The mixture was subjected to extraction with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 97 mg of 2-(4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl)-7-ethyl-7-methoxymethoxy-3-nonyn-2-ol having the following properties.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C]=O>O1CCCC1>[C:1]([C:4]1[O:5][C:6]([CH:11]=[CH:10][C:9]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(=O)c1ccco1
Agent: [C]=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(C)=O)o1
Reaction time: 7 h
Yield: 16 %

Procedure:
Charged in a stainless steel autoclave having an inner capacity of 200 ml were 5.5 g of 2-acetylfuran, 1.72 g of methyl acrylate, 0.038 g of Rh4 (CO)12 and 50 ml of tetrahydrofuran, followed by supply of carbon monoxide under 30 kg/cm2. Reaction was carried out at 220° C. for 7 hours. Tetrahydrofuran and unreacted 2-acetylfuran were removed from the obtained light brown solution by distillation under reduced pressure, and the residue was separated and purified by silica gel column chromatography. From a fraction eluted with methylene chloride was obtained 0.62 g of methyl β-(5-acetyl-2-furyl)acrylate (3) (the yield was 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:18])=[N:13][C:14](C(O)=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.FF>>[CH3:18][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][C:6]=3[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:8][CH2:9][C:10]2=[CH:14][N:13]=1
Reactant: Cc1nc(C(=O)O)c2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: FF
Product: Cc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Examples 1 and 2 were precisely repeated using the same moles of 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid as the ones of the derivative of formula (VI) having fluorine instead of the chlorine in position 2′. Climazolam was obtained with 80% titre (determined via HPLC titre correcting it using the solvent) and containing 2% of Isoclimazolam.
Reaction SMILES: C(NCC)C.[Li]CCCC.[C:11]([Si:15]([CH3:28])([CH3:27])[N:16]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]1=[O:26])([CH3:14])([CH3:13])[CH3:12].Br[CH2:30][CH2:31][CH:32]([Br:34])[CH3:33].[NH4+].[Cl-]>C1COCC1>[Br:34][CH:32]([CH3:33])[CH2:31][CH2:30][CH:18]1[CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]([Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:28])[CH3:27])[C:17]1=[O:26]
Reactant: CC(Br)CCBr
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC(Br)CCC1C(=O)N([Si](C)(C)C(C)(C)C)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To diethylamine (4.32 g, 59.0 mmol) in 22 mL of THF at 0° C. was added nBuLi (2.5 M in hexanes; 50.6 mmol, 20.2 mL). After 15 minutes the solution was added via cannula to a −50° C. solution of 1-(tert-Butyl-dimethyl-silanyl)-4-phenyl-azetidin-2-one (11.0 g, 42.2 mmol) in 110 mL of THF. After stirring for 20 minutes, 1,3-dibromobutane was added and the solution was stirred for 1 hour. Saturated aqueous NH4Cl was added and the mixture was warmed to room temperature and extracted once with ether. The extract was dried with MgSO4, concentrated and chromatographed (9:1 hexanes/EtOAc) to give 11.4 g (68%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ comp, 10H), 4.21 (d, J=2.5 Hz, 1H), 4.16 (d, J=2.5 Hz, 1H), 4.08 (m, 1H), 3.02 (m, 1H), 1.80–2.10 (comp, 4H), 1.67 (d, J=6.6 Hz, 3H), 0.90 (s, 9H), 0.18 (s, 3H), −0.22 (s, 3H); Mass spectrum m/e calcd for M+H=396.2. Found 396.0 (base), 316.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28]COC(C)=O.[N+](=C[Si](C)(C)C)=[N-].C(O)(=O)C>CO>[CH3:28][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Combined ethyl 5-hydroxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (0.6 g, 1.603 mmol), EtOAc (30 mL), and MeOH (10 mL) then added (diazomethyl)trimethylsilane, 2.0 M solution in hexanes (2.60 mL, 5.21 mmol) at 23° C. over 20 minutes. The reaction mixture was stirred at 23° C. for 1 hour, quenched with acetic acid (0.206 mL, 3.61 mmol), and the mixture was stirred for 2 hours at 23° C. The reaction mixture was concentrated to give an orange-brown oil which was purified by medium pressure chromatography using an eluent of 100% EtOAc on a 25 g silica gel column (Single Step™) to give the title compound (408 mg, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.27 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.62 (dd, J=12.88, 2.02 Hz, 2 H) 1.81 (ttd, J=11.13, 11.13, 7.31, 7.31, 3.79 Hz, 1 H) 3.20 (t, J=6.44 Hz, 2 H) 3.27 (td, J=11.68, 2.15 Hz, 2 H) 3.85 (dt, J=9.35, 2.27 Hz, 2 H) 4.14 (s, 3 H) 4.27 (q, J=7.07 Hz, 2 H) 7.79 (dd, J=8.34, 0.76 Hz, 1 H) 8.03 (s, 1 H) 8.38-8.43 (m, 1 H) 8.78 (t, J=5.81 Hz, 1 H) 8.98 (dd, J=2.53, 0.76 Hz, 1 H). MS m/z [M+H]+ 389.4.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:31][CH3:32])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:31]([N:12]1[C:13]2[CH:14]=[CH:15][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][C:18]=2[C:19]2[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]1=2)[CH3:32]
Reactant: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2

Procedure:
A mixture of 3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step I, 107 mg, 0.241 mmol) in methanol (20 mL, 1 drop concentrated hydrochloric acid) is treated with palladium on carbon (10%, 32 mg) and hydrogenated at 25 psi for 48 hr. The resulting mixture is filtered, rinsing with methanol and methylene chloride, and the filtrate is concentrated to a solid. The solid is purified via chromatography (10 g SG; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give the title compound, mp=224°, dec.; IR (drift) 2982, 2935, 2743, 1473, 1449, 1312. 1300, 1151, 1091, 819, 768, 728, 691, 647 and 623 cm−1; NMR (300 MHz, DMSO-d6) 8.09, 7.85-7.95, 7.45-7.65, 4.20, 2.95-3.25 and 1.15 δ; MS (EI) m/z 354 (M+), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS (FAB) calculated for C20H23N2O2S=355.1480, found 355.1488.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15]O>>[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15][O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(CCO)CC(C)(C)C
Reactant: CC(CC(=O)O)CC(C)(C)C
Product: CC(CCOC(=O)CC(C)CC(C)(C)C)CC(C)(C)C

Procedure:
The preparation from 3,5,5-trimethylhexanoic acid and 3,5,5-trimethylhexanol was analogous to Example 3; colorless liquid of medium viscosity; B.P. (1.3 mbar=134°-138° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1)#[N:9]
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 120 °C
Yield: 75.2 %

Procedure:
A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Example 337, 68.14 mg, 0.149 mmol) (3-fluorophenyl)boronic acid (62.5 mg, 0.446 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.05 mg, 7.44 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.27 mg, 0.015 mmol), and potassium phosphate (158 mg, 0.744 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (676 μl) and water (67.6 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. LCMS showed >95% conversion to the desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 7.5% MeOH/DCM). The resulting material was taken up in DCM, sonicated, filtered, washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (58.22 mg, 0.112 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J=1.9, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.6, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:58]1[N:63]=[C:62]([NH:64][C@H:65]2[CH2:70][CH2:69][CH2:68][CH2:67][C@H:66]2[NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[C:61]([F:79])=[CH:60][C:59]=1[C:80]#[N:81]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:58]2[N:63]=[C:62]([NH:64][C@H:65]3[CH2:70][CH2:69][CH2:68][CH2:67][C@H:66]3[NH:71][C:72](=[O:78])[O:73][C:74]([CH3:76])([CH3:77])[CH3:75])[C:61]([F:79])=[CH:60][C:59]=2[C:80]#[N:81])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C#N)cc1F
Reactant: Cc1cncc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(F)cc2C#N)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
5-methyl-3-pyridineamine (191 mg), cesium carbonate (1.10 g), Pd2(dba)3 (186 mg), and Xantphos (235 mg) were added to a 1,4-dioxane (14 ml) solution containing tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (500 mg), followed by stirring at 100° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. Insoluble matter was removed by filtration, the filter cake was washed with water and ethyl acetate, the organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:4), diisopropylether was added, solid matter was collected by filtration, and a light yellow solid of tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (523 mg) was thus obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:31])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=[O:29])=[CH:19][C:18]=1[F:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=[O:29])[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C@H:9]1[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]1)=[O:31]
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CN[C@@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 8 (0.329 g, 0.761 mmol) in anhydrous CH2Cl2 (5 mL) was added TFA (5 mL). The solution was stirred at RT for 0.5 h before concentrating under reduced pressure to reveal 9 (0.255 g, 100%) as a tan oil.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[C:2]2/[C:1](=[O:11])[C:10]3[C:5]([CH2:4][CH2:3]/2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1/C(=C/c2ccc(Br)cc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.9 %

Procedure:
A 250 mL flask was charged with tetralone (3.22 g, 22 mmol) and 4-bromobenzaldehyde (5.3 g, 28.6 mmol). This was dissolved in warm tetrahydrofuran (12 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (100 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (6.61 g, 96%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC=C(OC)C=2)[CH:6]=1.NCCCOC1C=C(OC)C=CC=1C(NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.[CH3:84][O:85][C:86]1[CH:87]=[C:88]([CH:91]=[CH:92][CH:93]=1)[CH:89]=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:89][C:88]2[CH:91]=[CH:92][CH:93]=[C:86]([O:85][CH3:84])[CH:87]=2)[CH:6]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2cccc(OC)c2)cc1
Agent: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2cccc(OC)c2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(3-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (26 mg, 0.042 mmol, 28%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 3-methoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.N.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:40][CH3:39])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Reactant: CCOP(=O)(C#N)OCC
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 534.17 (M+H).
Reaction SMILES: C1(S([N:10](C)[C:11](OCC)=[O:12])(=O)=O)C=CC=CC=1.[Cl:17][CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C([O-])(=O)C.O.CO.CN(C)C=O>O1CCOCC1>[Cl:17][CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:11](=[O:12])[NH2:10])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N(C)S(=O)(=O)c1ccccc1
Reactant: NC1CCC(Cl)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)NC1CCC(Cl)CC1

Procedure:
4.26 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl-methyl-urethane are heated for 1 1/2 hours in a reflux condenser in 100 ml dioxane with 2 g of 4-chlorocyclohexylamine-acetate. After addition of water and recrystallization of the precipitating product from methanol/dimethylformamide there is obtained in good yield the N-[4-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea melting at 177° -178°C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1O

Procedure:
4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid (1.98) was prepared from 5-bromosalicylic acid (2.6 g, 11.9 mmol ) and 4-nitrophenylboronic acid (3.0 g, 17.9) following general procedure D
Reaction SMILES: Cl([O-])(=O)=O.[Na+].[I-].[Na+].[CH3:8][C:9]1[CH:14]([OH:15])[CH2:13][CH2:12][C:11]([CH3:17])([CH3:16])[C:10]=1/[CH:18]=[CH:19]/[C:20](/[CH3:49])=[CH:21]/[CH:22]=[CH:23]/[C:24](/[CH3:48])=[CH:25]/[CH:26]=[CH:27]/[CH:28]=[C:29](\[CH3:47])/[CH:30]=[CH:31]/[CH:32]=[C:33](\[CH3:46])/[CH:34]=[CH:35]/[C:36]1[C:41]([CH3:43])([CH3:42])[CH2:40][CH2:39][CH:38]([OH:44])[C:37]=1[CH3:45].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:45][C:37]1[C:38](=[O:44])[CH2:39][CH2:40][C:41]([CH3:42])([CH3:43])[C:36]=1/[CH:35]=[CH:34]/[C:33](/[CH3:46])=[CH:32]/[CH:31]=[CH:30]/[C:29](/[CH3:47])=[CH:28]/[CH:27]=[CH:26]/[CH:25]=[C:24](\[CH3:48])/[CH:23]=[CH:22]/[CH:21]=[C:20](\[CH3:49])/[CH:19]=[CH:18]/[C:10]1[C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][C:14](=[O:15])[C:9]=1[CH3:8]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(O)CCC2(C)C)C(C)(C)CCC1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Temperature: 25 °C
Yield: 94872.4 %

Procedure:
An aqueous solution of 3.2 g of sodium chlorate and 20 mg of sodium iodide, dissolved in 20 ml of water, is added to 500 mg of racemic isozeaxanthin dissolved in 50 ml of chloroform, the two-phase mixture is stirred thoroughly at room temperature, and 5 ml of 0.01N sulfuric acid is added. After an hour, the mixture is neutralized with dilute sodium carbonate solution, the phases are separated, and the organic phase is washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure, 50 ml of heptane is added to the residue, and the whole is refluxed for 1 hour. After cooling, filtration gives 471 g (94% of theory) of canthaxanthin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].S(Cl)(Cl)=O.[CH3:17]N(C)C=O.O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(CC(=O)O)c1
Solvent: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
To a solution of 2-(3-cyanophenyl)acetic acid (1, 6.2 mmol) in methanol (20 ml) was added sulfurous dichloride (5 ml) and 0.1 ml N,N-dimethylformamide. Then the reaction mixture was heated to 80° C. for 2 h. When TLC indicated that the starting material was consumed, the mixture was concentrated to give the residue. The residue was poured into water (20 ml) and was extracted by ethyl acetate (50 m1*2). The organic layer was dried by anhydrous sodium sulfate, filtered, concentrated to give the desired product. LC-MS: m/z (M+H)=176.5
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([C:47]([F:49])([F:50])[F:48])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 331. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.81-7.68 (m, 3H), 7.42 (s, 2H), 4.78-4.68 (m, 1H), 4.45-4.26 (m, 1H), 4.14-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.88-1.76 (m, 1H), 1.76-1.65 (m, 2H). LCMS (ES+) m/z 517 (M+1).