Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=O.S(Cl)([Cl:30])=O>>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([Cl:30])=[O:20]
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetic acid and 48 parts of thionyl chloride was stirred for 1 hour at reflux temperature. The reaction mixture was evaporated, yielding 2.28 parts (100%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride as a residue (intermediate 32).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:17])=[CH:9][C:10]=3[F:16])[C:5](=O)[C:4]=2[CH:3]=1.[CH3:19][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:17])=[CH:9][C:10]=3[F:16])[C:5](=[CH2:19])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2c(F)cc(Cl)nc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c(F)cc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one (44 mg, 0.134 mmol) in 10 mL of dry THF was added dropwise methylmagnesium chloride (3M in THF, 0.12 mL, 0.335 mmol) in at −78° C. The reaction was slowly warmed up to 0° C. over 2 hours. The reaction was quenched at 0° C. with saturated NH4Cl (20 mL) and extracted with EtOAc (2×10 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. The derived tertiary alcohol was taken up in 10 mL of CH2Cl2 treated with 1 mg of PPTS. After stirring for 30 minutes the mixture was cooled to 0° C. and 0.1 g of NaHCO3 was added. The solvent was evaporated to dryness to give crude 8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine which was directly used in the next step. A solution of iodine (7.24 μL, 0.141 mmol) in THF at −25° C. was treated with silver cyanate (20.07 μL, 0.536 mmol). After stirring for 30 minutes, a solution of the derived olefin (8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine) in THF (10 mL) was added dropwise. The slurry was maintained at −25° C. for 2 h at which point the slurry was filtered through celite. The brown solution was concentrated to dryness, taken up in 10 mL THF, cooled to 0° C. and treated with ammonia (2M in 2-propanol (0.3 mL, 0.536 mmol). The reaction was allowed to slowly warm to rt and stirred overnight. The solvent was evaporated and the residue was purified by flash column (CH2Cl2 to CH2Cl2/EA=2:1 to 1:1 to CH2Cl2/MeOH=100:5) to give 8-bromo-2-chloro-4-fluoro-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as an off white solid.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([N:46](C([C@H]2N(C(C(O)C)=O)CCC2)=O)[CH3:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4].C(Cl)(Cl)Cl>CO>[CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([NH:46][CH3:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4]
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)NC)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O

Procedure:
A similar isolation scheme was employed later during large scale production of didemnin B for biological testing. The dichloromethane extract was obtained as before with only minor modifications due to scale-up. Prep LC employed an isocratic chloroform:methanol solvent system ranging from 98:2 to 96:4 depending on the condition of the reusable PrepPak cartridge. This allowed the use of the built-in refractive index detector to monitor elution of the didemnins. Fractions obtained through this procedure were chromatographed on a reversed phase (ODS) PrepPak cartridge with 77:23 methanol:water, again monitoring with the refractive index detector. Pooling of the appropriate fractions gave yields of didemnins A-C similar to those obtained with the original procedure. Didemnins D and E could only be separated by HPLC as above.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1.[CH2:29](I)[CH3:30]>>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:29][CH3:30])[CH:19]=2)[O:16][CH:17]=1
Reactant: CCI
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1O
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 270 and ethyl iodide, white powdery 1-(2-difluoromethoxyphenyl)-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:11]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8]1
Reactant: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1nn(C)c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To an acetonitrile (5 ml) solution of methyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (300 mg, 1.2 mmol) were added potassium carbonate (1.0 g, 7.4 mmol) and iodomethane (350 mg, 2.5 mmol) at room temperature respectively. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo. After being filtered off, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel chromatography column and eluted with a hexane/ethyl acetate=4/1 to furnish 239 mg (75% yield, major product) of the title as a white solid;
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=C(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)C=CC=1>>[F:29][C:3]1[CH:2]=[C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1

Procedure:
N-{6-[2-(3-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methanesulfonamide in Example 46 starting from 300 mg of 6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 54). The product was purified by passing through silica gel using ethyl acetate-heptane (5:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, 1H), 7.99 (dd, 1H, J 2.8, 0.6 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 6.98 (dd, 1H, J 8.8, 0.6 Hz), 6.90-6.88 (m, 3H), 5.16 (dd, 1H, J 10.0, 2.2 Hz), 2.99 (s, 3H), 2.96 (m, 1H), 2.72 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:49])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Br:20])=[CH:18][C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][C:15]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=[CH:6][C:5]=1[OH:48].[OH-].[Na+]>CCO>[Br:20][C:19]1[C:14]([O:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:49])=[O:2])=[C:5]([OH:48])[CH:6]=2)=[C:15]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH:16]=[C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=1
Reactant: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (1.16 mmol, 1 eq) in EtOH (20 mL) was added 1M NaOH (10 mL) and the reaction was heated at reflux 90 min. It was then cooled to rt, concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:Hexane+1% Formic acid) to afford the title compound (0.607 g, 79%) as a white foam. 1H NMR (DMSO-d6) δ13.55 (bs, 1H); 11,49 (bs, 1H); 8.58 (t, 1H); 8.14 (d, 1H); 7.90-7.84 (m, 3H); 7.73-7.61 (m, 3H); 7.26-7.12 (m, 5H); 6.27-6.23 (m, 2H); 4.00 (m, 2H); 3.92 (m, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2850, 1660, 1620, 1550, 1450, 1420, 1330, 1220, 1160, 1120 cm−1; mass spectrum [(−)ESI], m/z 726/728 (M−H)−; Anal. Calcd. for C37H37F3NO6: C, 60.99; H, 5.12; N, 1.92, Found: C, 60.32; H, 5.17; N, 1.83.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].O>CN(C=O)C>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][N:2]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: O=c1[nH]cc(-c2cnccn2)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnccn2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A mixture of 5-pyrazin-2-yl-1H-pyrimidine-2,4-dione hydrochloride (Prep125, 2.19 mmol), and K2CO3 (302 mg, 2.19 mmol) in DMF (20 ml) was stirred 30 minutes at room temperature. 90% 3-Bromo-1,1dimethoxy-propane (365 μl, 2.41 mmol) was added in two portions during 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 221 mg of the title compound (35% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][C:29]([NH:31][NH2:32])=O)=[CH:23][CH:22]=3)[CH:15]=[N:14]1>C(O)CCC>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][C:29]2[N:3]4[N:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]4=[N:32][N:31]=2)=[CH:23][CH:22]=3)[CH:15]=[N:14]1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cn1cc(-c2cnc3ccc(CC(=O)NN)cc3c2)cn1
Solvent: CCCCO
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(C(F)(F)F)nn45)cc3c2)cn1
Temperature: 120 °C
Yield: 30.8 %

Procedure:
A mixture of 1-butanol (2 mL), 3-chloro-6-trifluoromethyl-pyridazine (0.13 mmol, 25 mg), [3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]-acetic acid hydrazide (0.13 mmol, 40 mg) was heated at 120° C. for 18 hours. The solvent was then removed by blowing nitrogen, the brown residue dissolved in 1 ml of dimethylformamide and one 1 ml of methanol and purified by preparatory HPLC to return the title compound (15.8 mg, 0.04 mmol, 29%). Analytical data is presented in Table 2.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.I[CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:41]>O1CCCC1>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[N:28][C:27]=1[CH3:41])[CH3:6]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
A solution of ethyl acetate (2.24 ml, 22.8 mmol) in tetrahydrofuran (6 ml) was added to a −78° C. cold solution of LDA (2 M solution in tetrahydrofuran/n-heptane; 9.8 ml, 19.6 mmol) in tetrahydrofuran (15 ml) within 30 min under an argon atmosphere. The solution was stirred for 30 min at −78° C. and DMPU (3.9 ml, 32.6 mmol) was added within 20 min. A solution of 5-iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (2.5 g, 6.5 mmol) in tetrahydrofuran (15 ml) was added within 30 min and stirring was continued for additional 30 min. The mixture was naturally warmed to ambient temperature, stirred for one hour and poured onto aqueous ammonium chloride/ice water 1/1. Twofold extraction with ethyl acetate was followed by washing of the combined extracts with ice water/brine 1/1 (two times), drying over sodium sulfate and removal of the solvent under reduced pressure. The residue was purified by column chromatography (silica gel, heptane/AcOEt) and crystallized from heptane/dichloro-methane to yield 480 mg (1.4 mmol, 21%) of the title compound as light yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OC=C[O:19]3)=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(Cc2ccc(C3OC=CO3)cc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCN1C(=O)NC(Cc2ccc(C=O)cc2)C1=O

Procedure:
3-n-Butyl-5-[4-(1,3-dioxol-2-yl)benzyl] hydantoin (5.5 g., 0.017 mole) was dissolved in acetone (150 ml.) and stirred overnight at room temperature with p-toluene sulphonic acid (0.5 g). The acetone was evaporated off in vacuo and the residual oily solid partitioned between water and chloroform. The chloroform phase was washed with sodium carbonate solution (2% W/V), then evaporated in vacuo to give a yellow oil which slowly crystallised and was recrystallised from petroleum ether 60°/80° C./ethyl acetate (3/1 V/V) to give 3-n-butyl-5-(4-formylbenzyl) hydantoin, 4.5 g (95%), m.p. 160° C.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C>>[CH:19]([C:17]1[CH:16]=[CH:15][C:14]([O:22][CH3:23])=[C:13]([C:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[CH2:4][OH:3])=[CH:8][CH:9]=2)[CH:18]=1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(C(C)C)ccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(/C=C/CO)cc1

Procedure:
(E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl ester was reduced by DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-prop-2-en-1-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:17])=[C:7]3[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:15]1[CH2:14][CH2:13][CH2:12][C:8]2=[N:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6]([CH3:17])=[C:7]2[CH2:16]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(C)c3c(nc2c1)CCCNC3
Product: CCOC(=O)N1CCCc2nc3cc(C)ccc3c(C)c2C1
Yield: 42 %

Procedure:
8,11-Dimethyl-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 8,11-dimethyl-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 155.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[O-2].[Ca+2].[H][H]>[Pd].ClCCCl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)=[O:8]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCCl
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 70 °C

Procedure:
In an autoclave, there are charged 46 g (0.15 moles) of 3,3'-dinitro-4-chloro benzophenone, 11.2 g (0.2 moles) of calcium oxide, 1 g of 5% palladium/alumina catalyst (available from Nihon-Engelhardt Co.) and 250 ml of 1,2-dichloro ethane. With the mixture being stirred at a temperature of 30°-35° C., the reaction proceeds by the introduction of hydrogen for seven hours under a constant pressure of 10 Kg/cm2.G. After completion of the reaction, the reaction mixture is heated up to 70° C. for hot-filtering so as to remove the catalyst and the inorganic salt. On cooling, there is obtained 3,3'-diamino benzophenone as yellow needle-like crystals. The crystals are filtered, washed with 20 ml of 1,2-dichloro ethane and dried. Yield 24.8 g (78%). M.P. 149°-150° C. Recrystallization from ethanol gives yellow needle-like pure crystals of the benzophenone. M.P. 150°-151° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=3)[NH:8][C:7]=2[CH2:6]1)=O.[NH3:19]>CO>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:6][CH:5]([C:3]([NH2:19])=[O:2])[CH2:17][CH2:16][C:15]2=1
Reactant: N
Reactant: COC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Solvent: CO
Product: NC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 2.5 g. of methyl-6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylate, 20 g. of liquid ammonia and 150 ml. of methanol was placed in a pressure bottle. The mixture was shaken at 60° for 40 hours (internal pressure 60 lb/in2). Upon cooling to room temperature, the mixture was concentrated to dryness yielding 2.1 g. of product. Following a crystallization from ethyl acetate, 0.8 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid amide was obtained, m.p. 203°-204°.
Reaction SMILES: [CH3:1][C@:2]1([CH2:24][N:25]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[N:27]=[CH:26]2)[CH2:23][CH2:22][CH2:21][C:4]2(O[C@H](C3C=CC=CC=3)[C@@H](C3C=CC=CC=3)[O:5]2)[CH2:3]1>C(O)=O>[CH3:1][C@:2]1([CH2:24][N:25]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[N:27]=[CH:26]2)[CH2:23][CH2:22][CH2:21][C:4](=[O:5])[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Solvent: O=CO
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC(=O)C1
Temperature: 70 °C
Reaction time: 120 h
Yield: 77.7 %

Procedure:
A mixture of 1-{[(2R,3R,75)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (235 g, 508 mmol) in formic acid (1948 mL) was heated to 70° C. for 18 h, then the solution was concentrated under reduced pressure, and diluted with sat. NaHCO3 until it was basic. The resulting mixture was extracted with DCM (3×), and the combined extracts were washed with brine and then concentrated under reduced pressure. To the residue was added EtOAc (1 L) and then it was concentrated at 60° C. to a volume of approximately 750 mL. The slurry was then allowed to cool. Once solids started to form, the slurry was slowly diluted with 500 mL of hexanes and the temperature was raised to about 60° C. An additional 500 mL of hexanes was slowly added and the temperature was raised to reflux (about 68° C.). Once at reflux, heating was stopped, and the solution was allowed to cool to RT and stir for 5 days. Then the slurry was filtered, the solids were washed with hexanes and dried under reduced pressure to give 105.5 g of product (78% yield). The filtrate was concentrated and loaded onto silica gel and purified on a 220 g column (like a plug of silica) using vacuum to pull solvent through the column, and eluted with 500 mL of DCM, then 1 L of 50% EtOAc/DCM, then 1 L of 100% DCM, then 1 L each of 2.5%, 5%, 7.5%, and 10% MeOH/DCM. Fractions were collected in 1 L portions. Fractions containing product were concentrated to afford an additional 20.4 g (15% yield) of product. MS (m/z) 268.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:5].[O-:12][C:13]#[N:14].[K+].Cl>O>[CH3:1][O:2][CH2:3][C@@H:4]([NH:5][C:13]([NH2:14])=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[O-]
Reactant: COC[C@@H](N)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC[C@@H](NC(N)=O)c1ccccc1
Temperature: 100 °C

Procedure:
(S)-2-Methoxy-1-phenylethanamine (5.6 g, 37.0 mmol) and potassium cyanate (8.12 g, 100 mmol) were taken up in HCl (1 N, 40 mL, 40.0 mmol) and water (40 mL). The reaction mixture was heated to 100° C. for 3 h. Room temperature was attained, water was added, and the products extracted into EtOAc (×3) followed by 10% MeOH-DCM (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with Et2O to give (S)-1-(2-methoxy-1-phenylethyl)urea. MS ESI calc'd. for C10H14N2O2 [M+1]+ 195. found 195.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[NH2:16][C:4]1[S:3][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N:27]3[CH2:26][CH2:25][O:24][CH2:29][CH2:28]3)[CH:35]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Reactant: OB(O)c1cccc(N2CCOCC2)c1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CCOCC4)c3)sc2N)cn1
Yield: 59 %

Procedure:
Following Example 278, Suzuki coupling of (tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 3-morpholinophenylboronic acid gave 244 as a beige solid (56 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.25-6.95 (m, 4H), 6.07 (s, 2H), 3.92-3.88 (m, 7H), 3.24 (t, J=5 Hz, 4H). LCMS (ES+) m/z 385 (M+1)