Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([S:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C:14]([CH3:27])=[CH:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][CH:37]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][CH:37]([C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:38]([N:24]1[CH2:25][CH2:26][N:21]([C:20]2[C:15]3[C:14]([CH3:27])=[CH:13][N:12]([S:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)(=[O:10])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:22][CH2:23]1)=[O:39])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
The 7-benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (200 mg, 0.465 mmol) and 3-tert-butoxycarbonylamino-2-(4-chlorophenyl)-propionic acid (146 mg, 0.488 mmol) were dissolved/suspended in 2.0 mL of DMF at room temperature and treated with TEA (259 μL, 1.86 mmol). The HBTU (194 mg, 0.511 mmol) was added in one sum, and the reaction was allowed to stir overnight at room temperature to completion. The reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 70:30 ethyl acetate:hexanes) to afford the pure [3-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-3-oxo-propyl]-carbamic acid tert-butyl ester as colorless gel (295 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.49 (appt, J=7.6 Hz, 2H), 7.31 (m, 3H), 7.20 (d, J=8.0 Hz, 2H), 5.12 (m, 1H), 4.09 (m, 1H), 3.92 (m, 1H), 3.60 (m, 1H), 3.56-3.46 (m, 4H), 3.38 (d, J=10.4 Hz, 2H), 3.32 (m, 1H), 2.90 (m, 1H), 2.29 (s, 3H), 1.41 (s, 9H). LCMS (APCI+) m/z 639 [M+H]+; Rt=3.70 min.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCOc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)CCOc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 49 %

Procedure:
Using ethyl 3-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]propionate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 49%.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[C:16]([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28][C:27]1[CH:26]=[CH:25][C:24]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:35][CH:34]=1)=[O:4]
Reactant: N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)O
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 24 h
Yield: 18.3 %

Procedure:
Methyl trifluoroacetate (89.6 μL, 891 μmoles) and triethylamine (104 μL, 743 μmoles) were added to a suspension of 4-benzoylphenylalanine (200 mg, 743 μmoles) in methanol (0.5 mL). The reaction was stirred vigorously for 24 h and then acidified with 1 N HCl until a pH of 2 was obtained. The mixture was added to ethyl acetate (10 mL), washed with 1 N HCl (2×10 mL), dried over MgSO4, and concentrated in vacuo to yield a white solid (49.7 mg, 136 μmoles, 18%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([O:29]CC)=[O:28])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>C1COCC1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([OH:29])=[O:28])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)=O)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1

Procedure:
[5-(4-Acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [5-(4-acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetate (0.225 g, 0.529 mmol), and potassium hydroxide (0.104 g, 1.85 mmol) in THF (7 mL) and water (7 mL) according to the procedure described in Step 4 of Example 5. After drying for 15 hours at 96° C., the title compound was obtained as a tan solid (0.166 g, 79%), mp: 213-214° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 396; 1HNMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.05 (d, 2H, J=8.3 Hz), 7.8 (d, 2H, J=8.3 Hz), 7.7 (d, 1H, J=8.8 Hz), 7.65 (dd, 1H, J=8.7 Hz and 1.6 Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), and 2.6 ppm (s, 3H). Elemental Analysis for C25H19NO4.0.50 H2O: Calculated: C, 73.87; H, 4.96; N, 3.45. Found: C, 73.54; H, 4.64; N, 3.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>C(#N)C>[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:10](=[O:13])[N:9]([CH:14]2[CH2:16][CH2:15]2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12]1
Reactant: BrCc1ccccc1Br
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccccc2Br)nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
1.04 g (4.41 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 2.16 g (6.62 mmol) of cesium carbonate were suspended in 35 ml of acetonitrile, and 1.32 g (5.30 mmol) of 2-bromobenzyl bromide were added. The mixture was stirred under reflux for 18 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure. The solid that remained was stirred in about 50 ml of diethyl ether and then filtered off and washed with a little diethyl ether. Drying under reduced pressure gave 1.05 g (59% of theory) of the target compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])=[O:5])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH3:30])[CH:24]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([S:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][C:25]=2[CH3:30])[CH2:8][C@H:7]1[C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NCC#N
Reactant: Cc1cc(Cl)ccc1S
Product: CCOC(=O)[C@@H]1C[C@H](Sc2ccc(Cl)cc2C)C[C@H]1C(=O)NCC#N

Procedure:
The reaction of (1R,2R,4S)-2-(cyanomethyl-carbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester with 4-chloro-2-methyl-benzenethiol performed in analogy to example 1, step 5, yielded the title compound as a colorless solid. MS: 381.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3cscn3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3cscn3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 4-thiazolylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=1[C:11]([O-:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C[NH3+])C=CC=CC=1.C(C(CC)CNC1N=CC=CC=1[C:34](OCC)=[O:35])C>>[CH2:1]([N:8]1[C:9]2[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=2[C:11](=[O:13])[O:12][C:34]1=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: Cc1ccc(C(=O)[O-])c(NCc2ccccc2)n1
Agent: [NH3+]Cc1ccccc1
Product: Cc1ccc2c(=O)oc(=O)n(Cc3ccccc3)c2n1

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 62A for the product of Example 3A (0.150 g, 50%). 1H NMR (300 MHz, CDCl3) δ 2.66 (s, 3H), 5.47 (s, 2H), 7.10 (d, J=8.09 Hz, 1H), 7.31 (m, 3H), 7.55 (dd, J=7.54, 1.65 Hz, 2H), 8.26 (d, J=8.09 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3,4-dichlorophenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 447/449/451 ([M+H]+); 1H NMR (CDCl3) δ 9.22 (s, 1H), 8.52 (d, J=4.6 Hz, 1H), 8.18 (d, J=7.21 Hz, 1H), 7.96 (d, J=7.83 Hz, 1H), 7.84 (m, 2H), 7.61 (m, 1H), 7.42 (m, 3H), 7.13 (dd, J=8.25 and 1.97 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:10][OH:11]>CO>[CH3:1][CH2:2][C:3](=[N:10][OH:11])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)CC
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCCCC(CC)=NO

Procedure:
A mixture of 1-azabicyclo 2.2.1!heptan-3-one (8.83 g, 79 mmol) and hydroxylamine hydrochloride (5.52 g, 79 mmol) in MeOH (200 mL) was stirred at 25° C. for 18 hours. The solvent was removed under reduced pressure and the tan solid was partitioned between saturated Na2CO3 and CHCl3. The organic extracts were dried (Na2CO3), and concentrated to give the oxime, 5.48 g, 54.7%. The aqueous layer was concentrated, and re-extracted with CHCl3 to yield another 3.17 g product. Total yield, 8.65 g, 86%. The ratio is from 95% to 98% Z to E.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N+:17]([CH2:20][CH2:21][CH2:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:16][CH:15]=3)[N:10]=2)[CH2:8][CH2:7]1.CO.[BH4-].[Na+]>O>[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[OH:31])[CH2:16][CH:15]=3)[N:10]=2)[CH2:7][CH2:8]1
Reactant: O=C(CCC[n+]1ccc(-c2noc(C3CC3)n2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: OC(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1

Procedure:
To a 1.8 g. portion of 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1-[3-(p-fluorobenzoyl)-propyl]pyridinium perchlorate, prepared as described in Example 3, in 80 ml. of methanol is added, portionwise with stirring, 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into 300 ml. of cold water, causing a white solid to separate. This solid is collected and recrystallized from acetonitrile, m.p. 89°-92°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(Cc3cc(F)cc(F)c3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 1-chloromethyl-3,5-difluoro-benzene gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:4]=1[C:5](Cl)=[O:6])[CH3:2].[NH2:22][C:23]([NH2:25])=[NH:24].Cl>COCCOC>[NH2:24][C:23]([NH2:25])=[N:22][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:11][C:3]=1[CH2:1][CH3:2]
Reactant: N=C(N)N
Reactant: CCc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: Cl
Solvent: COCCOC
Product: CCc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.6 g of 2-ethyl-4-piperidino-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-ethyl-4-chloro-5-methylsulfonylbenzoic acid with excess piperidine followed by chlorination with SOCl2 ] dissolved in 60 ml of ethylene glycol dimethyl ether are added dropwise to a solution of 8.7 g of guanidine in 60 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 25° for one hour. 200 ml of ice-water are then added to the reaction mixture, which is acidified with 1N HCl, and subjected twice to extraction with 100 ml of ethyl acetate each time, and the organic phase is discarded. The aqueous phase is rendered alkaline with 1N NaOH and cooled. The product which precipitates is filtered off with suction to give N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 218°-220°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.C(O)(=O)CCCCCCC.C(OC(=O)C)(=O)C>>[CH3:28][C:6]1[C@@H:7]2[C@:12]3([CH3:27])[C@@H:11]([CH2:10][C@@H:8]2[O:9][C:5]=1[CH2:4][CH2:3][C@H:2]([CH2:30][OH:29])[CH3:1])[C@@H:16]1[CH2:17][CH:18]=[C:19]2[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]2([CH3:26])[C@H:15]1[CH2:14][CH2:13]3
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: CCCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1=C(CC[C@@H](C)CO)O[C@H]2C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@@H]12
Yield: 87 %

Procedure:
In a study of the degradation of a number of sapogenins at the Glaxo Laboratorties in UK, good results were obtained by heating diosgenin in refluxing n-Octanoic acid (bp 237° C.) containing acetic anhydride, distilling off the low boiling fraction until the temperature reached 270° C. and refluxing for 2 hours followed by saponifications resulting in the production of pseudodiosgenin in a yield of 87% (Ref:Cameroon AFB, Evans RM, Hamlet JC, Hunt JS, Jones PG and Long AG, J Chem Soc, 2807 1955.)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[NH2:35][CH2:36][C@@H:37]([OH:39])[CH3:38]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:35][CH2:36][C@@H:37]([OH:39])[CH3:38])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: C[C@H](O)CN
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNC[C@H](C)O)CC2)c1=O

Procedure:
3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 100 mg) and (S)-(+)-1-amino-2-propanol (0.247 mL) were stirred together in dioxane (3 mL) in a sealed tube at 100° C. for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) afforded the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][CH:23]=[O:24])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl.O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([C:13](=[O:15])[NH:31][C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][CH:23]=[O:24])[CH2:18]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(OC=O)C2)C(=O)O)cc1Cl
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(OC=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-formyloxy-cyclopentyl)-propionic acid (380 mg, 1.01 mmol) in toluene (10 mL) at 0° C. was treated with N,N-dimethylformamide (0.008 mL) followed by a 2.0M solution of oxalyl chloride in methylene chloride (0.75 mL). The reaction mixture was allowed to stir at 0° C. for 30 min and at 25° C. for 1.5 h. It appeared that a thick oil in the bottom of the reaction flask never solubilized. Additional methylene chloride (10 mL) was added at 25° C. followed by N;N-dimethylformamide (0.002 mL) and oxalyl chloride (0.3 mL). The reaction mixture was stirred at 25° C. for an additional 45 min and then concentrated in vacuo. The residue was dissolved in dry tetrahydrofuran (5 mL) and cooled to 0° C. This cold solution was then treated with a solution of 2-aminopyrazine (142 mg, 1.5 mmol) and pyridine (0.121 mL, 1.5 mmol) in dry tetrahydrofuran (5 mL) via a cannula. The resulting reaction mixture was stirred at 0° C. for 1 h and then diluted with methylene chloride (100 mL). The organic layer was successively washed with a 1M aqueous citric acid solution (2×100 mL), a saturated sodium bicarbonate solution 1×100 mL), and a saturated sodium chloride solution 1×100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford formic acid 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-2-(pyrazin-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (375 mg, 82%) as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:24]1[C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2c(Cl)cccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a solution of [(S)-1-(4-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.40 g, 3.76 mmol) in DCM (20 mL) was added TFA (20 mL) and the resulting mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous layer was further extracted with DCM and the combined organic layers were then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording (S)-1-(4-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a white solid (680 mg, 67%). LCMS: RT 2.23 min [M+H]+ 272.1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=2)=[O:29])[C:10]1=[O:42])=[O:7].O.[OH-].[Li+].O1CCCC1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:12][CH:11]([NH:27][C:28](=[O:29])[NH:30][C:31]2[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=2)[C:37]([OH:39])=[O:38])[C:10]1=[O:42])=[O:7]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccco3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C(C)(C)C
Yield: 61.8 %

Procedure:
1-[1-(Furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (187 mg) was dissolved in methanol (8.8 ml), aqueous lithium hydroxide monohydrate (68.3 mg) solution (4.4 ml) and tetrahydrofuran (4.4 ml) were added, the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid,and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 110 mg of the titled compound.
Reaction SMILES: [CH3:1][CH:2]([NH:11][CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC1C=CC2S(=O)C3C=C(C(O)=O)C=CC=3C=CC=2C=1>C(O)C>[CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC(C)C(O)c1ccccc1
Agent: O=C(O)c1ccc2c(c1)S(=O)c1ccc(F)cc1C=C2
Solvent: CCO
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Reaction time: 8 h

Procedure:
In a 5 liter flask containing ethanol (3.4 liters) is introduced 1-ephedrine (143.2 g.; 0.868 mole). Racemic 8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide (250 g.; 0.868 mole) is added rapidly to this solution and brought to reflux. After the addition, the reflux is continued until complete solution is obtained. The resulting solution is then left at room temperature overnight. The crystals are filtered, washed with a small volume of ethanol and air dried to yield the ephedrine salt of the title product having an enantiomeric purity of 93% (134.2 g.; 68%).