Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:3].[CH2:11]([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH2:29][C:30]([N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])[C:23](=[O:28])[CH2:24][N:25]=[C:26]=[O:27])=[O:15])[CH3:12]>>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:7][C:26](=[O:27])[NH:25][CH2:24][C:23]([N:22]([CH2:29][C:30]([N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[O:28])[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: CC(O)c1cccc(N)c1
Reactant: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN=C=O
Product: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(C(C)O)c1
Yield: 59.9 %

Procedure:
Using a procedure similar to that described in Example 31, but starting with 3-(1-hydroxyethyl)aniline (0.86 g) and 2-[N-(2-ethoxycarbonylphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (2.8 g), and after recrystallisation in ethyl acetate, 2-[2-{3-[3-(1-hydroxyethyl)phenyl]ureido}-N-(2-ethoxycarbonylphenyl)acetamido]-N-methyl-N-phenyl acetamide (2 g), m.p. 195° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]([CH3:8])[C:6]#[N:7].[C:13](O)(=O)[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>C1(C)C(C)=CC=CC=1>[OH:15][CH:14]([C:13]1[O:12][C:11]2[CH:10]=[CH:9][C:4]([CH:5]([CH3:8])[C:6]#[N:7])=[CH:3][C:2]=2[N:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C#N)c1ccc2oc(C(O)c3ccccc3)nc2c1

Procedure:
A mixture of 3-amino-4-hydroxyhydratroponitrile (10 g.), mandelic acid (14 g.) and xylene (300 ml.) was heated using a Dean and Stark apparatus for 24 hours. The solution was filtered, evaporated to dryness and the residue dissolved in chloroform. The solution was washed with acid and base, dried over sodium carbonate and was eluted down a silica gel column with ether to give 2-[2-(α-hydroxybenzyl)-5-benzoxazolyl] propionitrile, the structure of which was confirmed by n.m.r. spectroscopy.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O)=[N+]=[N-].S(Cl)([Cl:24])=O>>[Cl:24][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:1]=[C:4]2[C:5]=1[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19]2
Reactant: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(Cl)c2cc1F
Yield: 94 %

Procedure:
2-Azido-N-(4-chloro-phenyl)-4,5-difluoro-benzamide (18.5 g, 60 mmol) was suspended in thionyl chloride (193 ml). The suspension was heated under reflux conditions for 14 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. Under ice cooling saturated NaHCO3 solution was added until pH 8 was reached. The mixture was extracted two times with dichloromethane, the combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from methanol/dichloromethane/n-heptane to give the title compound (16.8 g, 56 mmol; 94%) as off-white crystals. MS: m/e=299.5 [M+H+].
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11]([C:18]1([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][CH:21]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1(Cc2ccccc2)CCC(NC2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
266 mg 1-aminoindane and 462 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in dry 1,2-dichloroethane under argon and the solution was stirred with 2 g sodium sulfate for 24 hours at RT. 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for two hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate. 696 mg 1-benzyl-N′-indan-1-yl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a colorless oil. For preparation of the hydrochloride, the base was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic hydrochloric acid (2.80 ml) was added. The solid which had precipitated out was filtered off with suction and dried. 540 mg of a mixture of cis- and trans-1-benzyl-N′-indan-1-yl-N,N-dimethyl-cyclohexane-1,4-diamine dihydrochloride were obtained as a white solid (m.p. 170-172° C.)
Reaction SMILES: [Li][CH2:2]CCC.[Si:6]([O:13][CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CI>C1COCC1>[Si:6]([O:13][CH:14]1[CH2:15][CH2:16][C:17]([CH3:2])([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8]
Reactant: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of anhydrous DIPA (26.7 g, 263.86 mmol, 3.00 equiv) in freshly distilled THF (500 mL) was added n-BuLi (2.5 M in hexane, 110 mL) dropwise with stirring at −78° C. under nitrogen. After the addition, the resulting solution was stirred for 0.5 h at −78° C. To this was added dropwise a solution of methyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate (24 g, 88.09 mmol, 1.00 equiv) in 50 mL of THF and the resulting solution was allowed to react for an additional 1 h at −78° C. To the mixture was added CH3I (62.64 g, 441.31 mmol, 5.01 equiv) dropwise with stirring at this low temperature. Stirring was continued for 1 h. The reaction was quenched with water and extracted with 3×150 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10) to provide the desired methyl 4-[(tert-butyldimethylsilyl)oxy]-1-methylcyclohexane-1-carboxylate (22.0 g, 87%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH2:1])[CH:4]=3)[NH:8][N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 88.7 %

Procedure:
To a solution of 300 mg of tert-butyl 5-(aminomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 1 ml methylene chloride was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 6.5 hours. After removing the solvent by filtration, to the residue was added 20 ml of ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 188 mg of the title compound as yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[CH:11][C:10]2[C:13]3([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH:14]3[CH2:15][CH2:16][CH2:17][C:9]=2[CH:8]=1)(=O)=O.[CH:35](/B(O)O)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][C@@:13]12[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C:9]1[CH:8]=[C:7](/[CH:35]=[CH:36]/[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:12]=[CH:11][C:10]=12
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=S(=O)(Oc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C(=C/c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3)\c1ccccc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
A flask with stir bar and nitrogen line was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl trifluoromethanesulfonate (144, R2=Pyridin-2-ylmethyl) (9.14 g, 18.34 mmol) (assumed 100% for previous reaction), (E)-styrylboronic acid (3.39 g, 22.9 mmol), cesium carbonate (14.94 g, 45.9 mmol), 1,4-dioxane (130 mL), water (32.5 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.644 g, 0.917 mmol). The mixture was warmed in an oil bath heated to about 90° C. for about 30 min. The mixture was cooled then concentrated under reduced pressure. The material was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated then the organic solution was washed with brine (75 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using 100% EtOAc. Product fractions were combined and concentrated under reduced pressure to yield (7aR,11aS)-11a-(pyridin-2-ylmethyl)-3-((E)-styryl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane] (145, R2=Pyridin-2-ylmethyl) (6.15 g, 74%); LC/MS, method 3, Rt=2.50 min, MS m/z 453 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.59-7.52 (m, 3H), 7.38-7.35 (m, 2H), 7.33-7.05 (m, 4H), 6.97-6.94 (m, 1H), 6.23 (s, 1H), 4.04-3.90 (m, 4H), 3.49 (d, J=13.8 Hz, 1H), 3.39-3.29 (m, 1H), 3.25 (d, J=13.3 Hz, 1H), 2.97-2.89 (m, 1H), 2.28-2.20 (m, 1H), 2.11-1.96 (m, 4H), 1.92-1.86 (m, 1H), 1.84-1.70 (m, 2H), 1.69-1.48 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][C:22]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxybenzyl alcohol and triethylamine in dichloromethane was added 4-bromobutyryl chloride at 0° C. The mixture was stirred at 0° C. for 30 minutes, and the solvent was evaporated. The residue was diluted with ethyl acetate, and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The concentrate was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=[O:15])[CH2:10][NH:9][CH2:8][CH2:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc2c(cc1C=O)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C=O)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrochloride (114 mg, 0.5 mmol) and freshly dried K2CO3 (173 mg, 1.25 mmol) in anhydrous dimethylformamide (5 mL), benzyl chloride (69 μL, 76 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was poured into water (25 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (3×5 mL), dried over MgSO4 and concentrated. The title compound (112 mg, 0.40 mmol, 80%) was obtained as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])C1C=CC(B(O)O)=CC=1>>[F:21][C:22]([F:33])([F:32])[C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1NCCc2c(-c3ccc(C(F)(F)F)cc3)[nH]c3cccc1c23

Procedure:
In a manner analogous to the method described above for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were coupled to yield 2-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 261 mg (70%), as an off-white solid. mp 208-209° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.09 (m, 2H), 3.40 (m, 2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (dd, 1H, J=8.1, 0.9 Hz), 7.71 (dd, 1H, J=7.5, 0.6 Hz), 7.88 (m, 4H), 8.13 (br t, 1H), 11.77 (br s, 1H); MS (FAB, MH+) 331; Anal. (C18H13F3N2O.1.0 H2O) C, H, N.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: C#CC(=O)OCC
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: CCOC(=O)C=CN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
400 mg (1.01 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.03 ml (10.1 mmol) of ethyl propiolate are heated at 120° C. in 7.5 ml of methylglycol for 1 hour. The reaction solution is concentrated in vacuo and the residue is stirred with water and filtered off with suction. The resulting crude product is recrystallized from ethanol.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:30])[C:15]([C:28]#[N:29])=[CH:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][C:11]=2[N+:31]([O-])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C1COCC1.C(O)C.[Pd]>[NH2:31][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:16]=[C:15]([C:28]#[N:29])[C:14]2=[O:30]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc(N)c(NCCN3CCOCC3)cc21
Yield: 110.3 %

Procedure:
A suspension of 916.4 mg (1.93 mmol) of 7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-([2-(trimethylsilyl)ethoxy]methyl)-1,4-dihydro-3-quinolinecarbonitrile in 52 mL of THF and 19 mL of ethanol is hydrogenated in a Parr apparatus at 40 psi for 6 hours in the presence of 183.3 mg of 10% palladium-on-carbon. The catalyst is removed by filtration and the solvent is evaporated in vacuo to give 944.0 mg of 6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile as a deep yellow solid which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(-c4ccccc4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[CH:5]=[CH:4][N:3]=1.[CH2:14]([Zn]CC)[CH3:15].O.Cl>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:14][CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)ccnc1CC
Temperature: 40 °C
Yield: 63 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (1.5 g, 5.7 mmol) was dissolved in anhydrous dioxane (45 mL). A solution of diethyl zinc (4.6 mL, 5.1 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (62 mg, 85 mol). The mixture was heated at 40° C. overnight, and then water plus 1 N HCl were added. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-15% hexane/ethyl acetate to afford ethyl 4-chloro-2-ethylpyridine-3-carboxylate (687 mg, 57% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:22][CH2:23][OH:24])[C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=1F)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CN(C=O)C>[CH2:3]([N:10]1[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[O:24][CH2:23][CH2:22]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(F)c(F)c1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(F)c(F)c2OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
Sodium hydride (25 mg, 0.615 mmol, 60% dispersion in mineral oil) was added slowly to a solution of N-benzyl-2,3,4-trifluoro-N-(2-hydroxyethyl)benzamide (190 mg, 0.615 mmol) in DMF (3 mL) and the pale yellow solution was stirred at RT for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (4×30 mL). The combined organic phases were washed with water (3×20 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as a colourless oil (130 mg). 1H NMR δ (CDCl3): 3.5 (t, 2H), 4.3 (t, 2H), 4.8 (s, 2H), 6.92 (dd, 1H), 7.3-7.4 (m, 5H), 7.7 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCCOc1ccc2c(c1)OCO2
Product: CCOC(=O)N1CCC(c2cn(CCOc3ccc4c(c3)OCO4)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 9.6 g (48 mmol) of 5-(2-chloro-ethoxy)-benzo[1,3]dioxole. The mixture was stirred at room temperature for 18 hours. After standard work-up and purification, 10.5 g (60% of yield) of 4-{1-[2-(benzo[1,3]dioxol-5-yloxy)-ethyl]-1H-indol-3-yl}-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11])[CH2:3][O:4][CH3:5]>C(O)C>[OH:23][C:21]1[CH:20]=[C:9]([CH:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][O:4][CH3:5])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Solvent: CCO
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
3-{[(1S)-1-Methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (4.5 g, 11 mmol) was dissolved in ethanol (35 mL) and THF (35 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (0.45 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite, and the filtrate concentrated in vacuo to give the desired compound (3.21 g).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[O:24]1[CH2:26][CH:25]1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[OH:24])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cc(C2CO2)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.4 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (600 mg, 2.643 mmol) was dissolved in DMF (18 mL), and cooled to 0° C. Potassium tert-butoxide (444 mg, 3.964 mmol) was added and stirred for 5 min. 4-Oxiranyl-pyridine (639 mg, 5.286 mmol) in DMF (3 mL) was added dropwise into the reaction mixture and the mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (4×70 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 400 mg of 2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.8 (d, 2H), 8.2 (d, 2H), 8.1 (s, 1H), 7.9 (s, 1H), 5.38 (m, 1H), 5.09 (t, 1H), 4.68 (dd, 2H), 4.4 (m, 1H), 3.75 (m, 4H), 3.43 (m, 2H), 2.7 (m, 2H), 2.46 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC provided diastereomers IV-209a-d.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[OH:26])[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[OH:26])[P:16]([OH:18])[OH:17]
Reactant: Oc1ccc(C(NC(c2ccccc2)c2ccccc2)P(O)O)c(O)c1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(c1ccc(O)cc1O)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(2,4-dihydroxyphenyl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(2,4-dihydroxyphenyl)-methanephosphonous acid.