Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[CH:17][CH:18]=3)[N:11]=[C:10]([C:21]([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 110A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. In order to remove the 1,1′,1″-phosphoryltripyrrolidine the product is taken up in a little tetrahydrofuran, water is added to the mixture until a precipitate forms, the tetrahydrofuran is removed in vacuo, and the precipitate is collected by suction filtration and dried under high vacuum. 42 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:29]=[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26](O)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]2[N:10]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:29]=[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26]([N:30]3[CH2:33][CH2:32][CH2:31]3)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CNC1
Product: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 44.4 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (75 mg, 191 μmol) and azetidine (51.5 μl, 765 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (36.6 mg, 44.4%) off-white solid. mp.: 258.1° C., MS: m/z=432.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+]([O-])=O)[NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=1)=[O:3].[C:43]([OH:46])(=[O:45])[CH3:44]>[Pd]>[NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:41])[NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=1)=[O:3].[C:43]([O-:46])(=[O:45])[CH3:44]
Reactant: NC(=O)NCc1cccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)[O-]
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1cccc(CNC(N)=O)c1
Yield: 42 %

Procedure:
Prepared analogously to Example 4c) from (R)N-[[3-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino]methyl]-N2 -(diphenylacetyl)-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% acetic acid in a yield of 42% of theory.
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:49]1[C:57]2[C:52](=[N:53][CH:54]=[CH:55][CH:56]=2)[N:51]([CH2:58][CH2:59]O)[CH:50]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:4]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][N:31]([CH2:59][CH2:58][N:51]3[C:52]4=[N:53][CH:54]=[CH:55][CH:56]=[C:57]4[N:49]=[CH:50]3)[S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:33])=[O:34])([CH3:10])[CH3:11])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reactant: OCCn1cnc2cccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCn2cnc3cccnc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reaction time: 2 h
Yield: 299.4 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-2,4-dinitrobenzenesulfonamide (0.415 g in 6 mL benzene) was added 0.20 g 2-imidazo[4,5-b]pyridin-3-yl-ethanol followed by 0.32 g triphenylphosphine and 0.189 mL of diethyl azodicarboxylate added dropwise. After 2 hours, the mixture was concentrated and the crude reaction product purified by flash chromatography on silica gel (methylene chloride:methanol, 98:2; then 95:5) to give the title compound (1.51 g).
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH:12]=[CH:11]N=[CH:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.NC1[C:22]2C(=[N:18][CH:19]=[C:20]([Cl:37])[C:21]=2[N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)NC=1.[CH2:38]1COCC1>CCOC(C)=O>[Cl:37][C:20]1[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[C:22]2[C:5]([NH:1][C:6]([N:8]3[CH2:9][CH2:38][CH2:11][CH2:12]3)=[O:7])=[CH:4][NH:3][C:2]2=[N:18][CH:19]=1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)N4CCCC4)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Di(1H-imidazol-1-yl)methanone (2185 mg, 13.5 mmol) was added to a stirring solution of crude (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (986 mg, 2.70 mmol) in THF (10 mL), and the mixture was stirred at room temperature. After 18 hours, the reaction mixture was concentrated in vacuo. The residue obtained was dissolved in EtOAc (100 mL) and washed with water (4×20 mL) and brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-85% CH3CN/water). The product was extracted from the aqueous phase into EtOAc (3×50 mL). The combined organic layers were washed with water (2×10 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide (R)-tert-butyl 1-(5-chloro-3-(pyrrolidine-1-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (920 mg, 74% yield) as a solid. LCMS (APCI+) m/z 463.1 (M+H)+.
Reaction SMILES: ClN1C(=[O:7])CCC1=O.[OH:9][C@@H:10]1[C@@H:32]([N:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)[CH2:31][C@@:30]2([CH3:41])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:29]2[C:28](=[O:42])[CH2:27][C@@:26]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=NCCO)[CH3:21])[CH2:11]1.[ClH:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[Cl:44][CH2:21][C:20](=[O:7])[C@@H:19]1[C@:26]2([CH3:43])[C@H:16]([C@H:15]3[C@H:29]([C:28](=[O:42])[CH2:27]2)[C@:30]2([CH3:41])[C@H:12]([CH2:11][C@H:10]([OH:9])[C@@H:32]([N:33]4[CH2:38][CH2:37][O:36][C:35]([CH3:39])([CH3:40])[CH2:34]4)[CH2:31]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1
Reactant: Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=NCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Chlorosuccinimide (2.16 g) was added to a solution of (2β,3α,5α)-3-hydroxy-20-[(2-hydroxyethyl)imino]-2-(2,2-dimethyl-4-morpholinyl)pregnan-11-one (8.77 g) in tetrahydrofuran (175 ml). The solution was stirred at room temperature for 2 h and hydrochloric acid (53 ml; 1M) was then added. After stirring at room temperature for 1.25 h, the reaction mixture was poured into water (1 l). The pH was adjusted to 9 with aqueous sodium carbonate and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying over sodium sulfate, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from diethyl ether to give (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (3.23 g). m.p. 206°-208° C. (dec); [α]D +130.5° (c 0.57).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:24]=2)(=[O:18])=[O:17])[CH:7]=1.[Li+].[OH-].CCCCCC.C(OCC)(=O)C.Cl>O1CCCC1>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH:24]=1)(=[O:17])=[O:18])[CH:7]=[C:6]2[CH2:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2cncc(-c3ccc(C(F)(F)F)cc3)c2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cn(S(=O)(=O)c2cncc(-c3ccc(C(F)(F)F)cc3)c2)c2ccc(Cl)cc12

Procedure:
The 3-{5-chloro-1-[5-(4-trifluoromethyl-phenyl)-pyridine-3-sulfonyl]-1H-indol-3-yl}-propionic acid methyl ester 13 (20 mg, 0.00038 mol) was dissolved in 4 mL mixture of tetrahydrofuran:1N LiOH (4:1) and stirred vigorously overnight. TLC (20% ethyl acetate hexane) indicated absence of starting material and a new spot. The reaction was acidified by adding 1N HCl (pH 0-1 by pH paper) and extracted with 12 mL of ethyl acetate, which was dried over MgSO4. A silica plate was carried out using 2% methanol/chloroform to isolate the desired compound. 1H NMR consistent with structure. MS(ESI) [M−H+]−=507.02 (calculated 508.90).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (276 mg, 1.08 mmol) [Prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (317 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (612 mg, 1.31 mmol) in Chloroform (14 mL). DIEA (940 μL, 5.38 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[N:20](COCC[Si](C)(C)C)[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2COc3ccc(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of (S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.016 mmol) in a solution of TBAF in THF (1 M, 20 mL, 20 mmoL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water (25 mL). The aqueous solution was extracted with EtOAc (3×25 mL). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrate in vacuo to give the residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum) to give (S)-3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 54%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.05 (m, 1H), 6.94-6.77 (m, 1H), 6.53-6.23 (m, 2H), 4.74-4.46 (m, 3H), 3.62-3.30 (m, 4H), 2.32-2.17 (m, 1H), 2.00-1.86 (m, 1H), 1.59-1.44 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:15]O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:12]=[N:15][O:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(C=O)C=O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cnoc2)cc1
Reaction time: 8 h

Procedure:
The (4-methoxyphenyl)malonaldehyde (2.5 g, 14 mmol) was heated under reflux with hydroxylamine hydrochlorid (1.46 g, 21 mmol) in ethanol (28 mL) for 2 hours. Ethanol was removed under vacuum and the residue was purified by column chromatography through a 115 gram biotage silica gel cartridge eluting with 20-50% EtOAc/hexanes to give pale oil, which solidified upon standing overnight.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(OCC)(=O)C>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:4]([OH:21])[CH2:3][O:2][S:26]([CH3:25])(=[O:28])=[O:27])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Temperature: 5 °C
Yield: 200.5 %

Procedure:
N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-butyric acid methyl ester 340.4 kg was reduced with sodium borohydride by the same way as described in Reference Example 3, to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol, which was dissolved in ethyl acetate 988 kg. To the solution were added methane sulfonylchloride 130.7 kg at 15-0° C. and triethylamine 115.4 kg, successively, and the solution was stirred at 20-30° C. for 15 min. The reaction solution was washed with aqueous 5% sodium bicarbonate solution to separate an organic phase, which was washed with aqueous 10% sodium chloride solution. The separated organic phase was mixed with n-heptane and cooled gradually down to 5° C. or lower to deposit crystals, which were filtered by a Nutsche funnel to obtain a wet crystal of crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane 793 kg (Net.368.9 kg).
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:14])[C:5](=[O:13])[C:6]2[C:11]([CH3:12])=[N:10][NH:9][C:7]=2[N:8]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:2][C:3]3[N:4]([CH3:14])[C:5](=[O:13])[C:6]4[C:11]([CH3:12])=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1n[nH]c2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 6-mercapto-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium (800 mg) in DMF (12 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.05 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.086 g). 1H-NMR (DMSO-d6) δ: 2.44(3H,s), 3.42(3H,s), 4.60(2H,s), 7.63(2H,d,J=8.6Hz), 7.71(4H,s), 7.75(2H,d,J=8.6Hz), 13.29(1H,brs).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:17][CH3:18])[N:3]=1
Reactant: CCNc1ccncc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCN(c1ccncc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-pyridyl)-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-(ethylamino)pyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:20][C:21]1([CH3:30])[CH2:26][CH:25]([OH:27])[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1.[OH-].[Na+]>ClCCl.O>[C:1](=[O:17])([O:27][CH:25]1[CH2:26][C:21]([CH3:30])([CH3:20])[NH:22][C:23]([CH3:29])([CH3:28])[CH2:24]1)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCCCCCCCCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.7 g (0.1 mol) of tetradecyl chlorocarbonate are added slowly to a solution of 19.4 g (0.1 mol) of 2,2,6,6-tetramethyl-4-piperidinol hydrochloride in 150 ml of dichloromethane, maintaining the temperature at between 0° C. and 5° C. After the end of the addition, the mixture is stirred for 2 hours at ambient temperature, and a solution of 8.8 g (0.22 mol) of NaOH in 50 ml of water is then added slowly, with cooling to -10° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)=Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 2,5-dichlorbenzaldehyde (4.0 g, 0.0228 mole) in ethanol (6 ml) was added malononitrile (1.52 g, 0.0228 mole), followed by 100 μL of 10% KOH/H2O. The mixture was stirred at room temperature for 2 hrs and then filtered to give the title compound (4.82 g) in 95% yield. 1H-NMR (400 MHz, d6-DMSO): δ ppm 8.66 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 7.74 (s, 1H). MS [m+H] calc'd for C10H4Cl2N2, 223.0, 224.8; found 223.0, 224.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(/C(=C/C=O)c2ccccc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\c1ccccc1)c1ccc(OC)cc1
Yield: 80 %

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-3-phenyl-2-propenal (8.7 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (14.2 g) in carbon tetrachloride (50 mL) and dichloromethane (5 mL) overnight at room temperature. The crude ester was isolated in the usual manner and was purified by HPLC (ether-hexane; 3:17) to yield 8.6 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid methyl ester. Crystallization of a portion from ethyl acetate-hexane gave the analytical specimen, mp 88°-89.5° C. Anal. Calcd for C19H18O3 : C, 77.53; H, 6.19 Found: C, 77.40; H. 6.18
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2.7 g, 4.5 mmol) prepared in Example 5 was dissolved in THF (20 mL). Then aqueous solution (10 mL) of KOH (0.5 g) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl solution. The white solid was collected by filtration to give title compound (1.6 g).