Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=1)[C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][C:2]2=[O:20].Cl>CO.O.[Pt](=O)=O>[CH:14]12[NH:18][CH:1]([CH2:17][CH2:16][CH2:15]1)[C:2](=[O:20])[NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]2=[O:19]
Reactant: O=C1NCCNCCNCCNC(=O)c2cccc1n2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NCCNCCNCCNC(=O)C2CCCC1N2
Temperature: 60 °C
Yield: 73 %

Procedure:
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadeca-1(18),14,16-trien-2,13-dione prepared as in Example 38A (1.0 g, 3.6 mmol) was dissolved in methanol (75 ml) and concentrated hydrochloric acid (2.14 g, 21.7 mmol) was added, then the catalyst platinum dioxide hydrate (0.5 g, 2 mmol). The mixture was heated to 60° C. and hydrogenated at 60 psi for 24 h. A white crystalline solid formed during the hydrogenation. The reaction mixture was filtered, and the precipitate was washed with water to dissolve it. The filtrate was concentrated to remove the alcohol and sodium hydroxide (1.0 N) was added to raise the pH to 11. This solution was extracted five times with dichloromethane (75 ml each), the solvent was removed under reduced pressure, and the resulting white solid was dried on the vacuum line to give 0.74 g (73% yield) of product: mp 193-195.5° C. (dec); 1H NMR (CD2Cl2) δ 0.79-1.48 (several m, 5 H), 1.88 (m, 2 H), 2.01 (m, 2 H), 2.63-2.88 (several m, 8 H), 3.10 (m, 2 H), 3.24 (m, 2 H), 3.36 (m, 2 H), 7.71 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=423.1, tR (minutes, Method G)=2.58
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][NH2:20]>C(O)C.O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([CH3:18])[N:3]=[C:2]([NH:20][CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: CN
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(C)n1
Yield: 84 %

Procedure:
0.056 g (0.00017 mol) of 4-(2-bromo-6-methylpyridine-4-sulphonyl)-phenylamine and 1.1 ml of 8 M methylamine in ethanol were stirred at 120° C. in 5 ml of dioxane for 24 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. The product-containing fraction were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.04 g (84%) of [4-(4-aminobenzenesulphonyl)-6-methyl-pyridin-2-yl]-methylamine as light yellow crystals; m.p.: 126-127° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH2:6][CH:2]([NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: NC(Cc1cccc(Br)c1)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NC(Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a suspension of 2-amino-3-(3-bromophenyl)propanoic acid (11.0 g, 45.5 mmol) and NaHCO3 (11.5 g, 136.5 mmol) in THF (100 mL)/H2O (100 mL), ethyl 2-chloro-2-oxoacetate (18.4 g, 135.2 mmol) was added dropwise at 0° C. The mixture was stirred at RT overnight, acidified with aqueous critic acid (10%), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 3-(3-bromophenyl)-2-(2-ethoxy-2-oxoacetamido)propanoic acid as a colorless oil (5.2 g, 33%). MS (ES+) C13H14BrNO5 requires: 343, 345 found: 344 [M+H]+, 346 [M+2+H]+(1:1).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])C.[OH-].[Li+]>C1COCC1.O>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]([OH:27])=[O:3])[CH2:12][CH2:11]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1OC1CCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid ethyl ester (14.1 mmol, 5.3 g) in THF (140 mL) was added aqueous lithium hydroxide solution (1.0M; 17.6 mmol, 17.6 mL) in one portion at room temperature and the resulting homogeneous solution stirred overnight. The precipitated solution was diluted with H2O (150 mL) and the THF was removed in vacuo. The aqueous phase was diluted with saturated NaHCO3 (400 mL), and acidified with 2N HCl. The aqueous phase was then extracted with EtOAc (3×400 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The product was triturated with Et2O/hexane to yield the title compound as a white solid, mp=112°-113° C. (10.8 mmol, 3.74 g, 76%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])[C:14]([N+:26]([O-])=O)=[C:13]([F:29])[CH:12]=2)[CH2:6][S@@:5](=[O:30])[CH2:4]1.[CH3:31][C:32]1([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH:38]=O)[CH2:34][CH2:33]1>>[NH2:26][C:14]1[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[CH:16][C:11]([CH2:10][C@H:7]2[C@H:8]([OH:9])[C@@H:3]([NH:2][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([C:32]4([CH3:31])[CH2:33][CH2:34]4)[CH:36]=3)[CH2:4][S@:5](=[O:30])[CH2:6]2)=[CH:12][C:13]=1[F:29]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Reactant: CC1(c2cccc(C=O)c2)CC1
Agent: Cl
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cccc(C4(C)CC4)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound can be prepared in an analogous manner as described for example 41 steps c) and d) from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol hydrochloride and 3-(1-methyl-cyclopropyl)benzaldehyde to yield the title compound as a yellowish foam: TLC (CH2Cl2-MeOH 9:1) Rf=0.48; HPLC RtG3=1.70 min; ESIMS [M+H]+=559.3; 1H NMR (400 MHz, DMSO-d6): δ 7.22-7.18 (m, 2H), 7.11 (d, 1H), 7.07 (d, 1H), 6.72 (s, 1H), 6.64 (d, 1H), 5.09 (m, 1H), 4.99 (d, 1H), 4.58 (s, 2H), 3.75 (m, 3H), 3.59 (d, 1H), 3.32 (s, 3H), 3.19-3.09 (m, 3H), 2.98 (m, 1H), 2.69 (m, 1H), 2.45-2.25 (m, 4H), 1.36 (s, 3H), 0.83 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[N:2]1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:1]2[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]3[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=3)=[N:2]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccnc(OCCSc2nc[nH]n2)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
A solution of 2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridine-4-carbonitrile obtained in Reference Example 17 (3.40 g, 13.7 mmol), trityl chloride (5.73 g, 20.6 mmol) and triethylamine (2.87 mL, 20.6 mmol) in THF (30 mL) was stirred at room temperature for 15 hr. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (20%-40% ethyl acetate/hexane) to give the title compound as a white powder (5.37 g, 80%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:24][CH2:23][C@H:22]3[CH2:25][N:26](C(OCC)=O)[CH2:27][C@@H:21]23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[N:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:19]3)[CH2:24][CH2:23][C@H:22]2[CH2:25][NH:26][CH2:27][C@@H:21]12
Reactant: CCOC(=O)N1C[C@@H]2CCN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)[C@@H]2C1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CC[C@H]4CNC[C@H]43)cccc2c1
Yield: 21.8 %

Procedure:
A solution of (3aS,6aS)-ethyl 1-(3-(phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (60 mg, 0.133 mmol) and trimethylsilyl-iodide (160 mg, 0.797 mmol) in chloroform (1 mL) was stirred at reflux for 1.5 h. Methanol (4 mg) was added and the solution was partitioned between ethyl acetate and aqueous NaOH (1M). The organic extract was dried (MgSO4), filtered and concentrated to yield 11 mg (22%) of the title compound as a pale yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:23])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:22])[C@H:13]([CH:19]([CH3:21])[CH3:20])[NH:14][C:15]([O:17][CH3:18])=[O:16])(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:23])=[O:5])=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 120 °C
Yield: 55.3 %

Procedure:
To a solution of N-[methoxycarbonyl]-L-valyl-L-proline tert-butyl ester (813 g) in toluene (3 liters) was added Amberlyst-15 ion exchange resin (190 g). The reaction was heated at 120° C. to distill off water present in the resin via a water/toluene azeotrope. Approximately 400 ml of distillate was collected. Heating was then continued at reflux for 1.5 hours. The reaction was cooled to 60° C. and the resin was removed by filtration. The filtrate was extracted with 1M NaOH (2.5 liters) followed by saturated aqueous sodium bicarbonate solution. The combined basic extracts were extracted with a mixture of THF/ethyl acetate (1:1, 1 liter), and then cooled in an ice bath. The aqueous solution was made acidic to pH 1.5 using cold 3M hydrocloric acid (1 liter) and extracted twice with THF/ethyl acetate (1:1, 1.5 liters and 1 liter). The extracts were combined and washed with brine, dried (MgSO4), and the solvent removed by evaporation. The resulting material was dissolved in ether (1 liter) and allowed to crystallize at 0° C. over 48 hours. The resulting solid was collected by filtration, washed with cold ether and dried under vacuum to give N-[methoxycarbonyl]-L-valyl-L-proline (373 g); 1H NMR (300 MHz, DMSO) 12.4 (s, 1H), 7.37 (d, 1H), 4.25 (dd, 1H), 4.00 (t, 1H), 3.79 (m, 1H), 3.55 (m, 1H), 3.51 (s, 3H), 2.11 (m, 1H), 1.85 (m, 4H), 0.91 (d, 3H), 0.87 (d, 3H); MS m/z=273 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[Cl:14][C:15]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:11](=[O:12])[NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(=O)O)c1)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 200 mg 3-Isocyanato-benzoic acid methyl ester in 2 ml ethyl acetate is added dropwise a solution of 162 mg 2,4-dichloroaniline in 1 ml ethyl acetate. After 5 h at RT the solvent was removed under reduced pressure and the residue dissolved in 5 ml MeOH/THF/H2O 2:2:1. 100 mg lithium hydroxide monohydrate was added and the mixture stirred over night at RT. After removal of the solvent the residue was acidified by addition of 5 ml half concentrated HCl. The precipitating acid was filtered off and dried.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][S:32]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCS(=O)(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 g (8.6 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 2.4 g (17.2 mmol) of potassium carbonate were initially introduced into 40 ml of toluene. 1.5 g (9.5 mmol) of butanesulphonyl chloride were added dropwise, and the mixture was then stirred for a further 2 h at room temperature. The mixture was then filtered and evaporated in a rotary evaporator. After chromatography on silica gel 60, 40-63 μm, using diisopropyl ether/ethanol, 3:2, the product was recrystallized from petroleum ether.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][N+:4]([CH2:7][C:8]([NH:10][NH2:11])=[O:9])=[CH:3][CH:2]=1.[Cl-:12].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14]>>[Cl-:12].[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13](=[N:11][NH:10][C:8]([CH2:7][N+:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:9])[CH3:14]
Reactant: CC(=O)c1ccccn1
Reactant: NNC(=O)C[n+]1ccccc1
Agent: [Cl-]
Product: CC(=NNC(=O)C[n+]1ccccc1)c1ccccn1

Procedure:
Following the general method of Example 2 and making non-critical variations, 5.63 gm (0.03 mole) of Girard's Reagent P and 3.63 gm (0.03 mole) of 2-acetylpyridine yield 5.70 gm (65%) of the title compound; mp 183.7° (decomp).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.[Al].CC(C)[O-].C(O)(C)C>>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH:9]([OH:11])[CH3:10])=[CH:5][CH:6]=1
Reactant: CC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Agent: CC(C)[O-]
Agent: [Al]
Solvent: CC(C)O
Product: CC(O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 5 h

Procedure:
13.0 Gm (0.0585 mol) of (E)-4-(4-biphenylyl)-3-butene-2-one were gently refluxed with 12.5 gm (0.0612 mol) of aluminum-isopropoxide and 190 ml (2.48 mol) of isopropanol in a dry distillation apparatus with a 60-cm-Vigreux-column, in such a way that only about 5 drops were distilled off per minute. After about 5 hours no acetone was found to be present in the distillate (by use of hydrochloric 2,4-dinitrophenyl-hydrazine-solution). In the reaction mixture, columnchromatography showed no starting material was present. The isopropanol was distilled off in a weak vacuum, the residue was hydrolyzed by addition of 50 gm of crushed ice and 34 ml of 6 N hydrochloric acid. The reaction mixture was exhaustively extracted with ethyl acetate, the combined extracts were washed with water, with 5% sodium hydroxide solution and again with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized, once from cyclohexane/ethyl acetate (ratio by volume: 9:1) and once from benzene. Yield: 11.0 gm (84% of theory) of colorless crystals, m.p. 138°-139°C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([CH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[CH2:9][C:10]#[N:11]>C(O)(=O)C>[S:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[C:10]([NH2:11])[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=2)[CH2:13][CH2:14]1
Reactant: Nc1cc[nH]n1
Reactant: N#CCC(=O)C1CCSCC1
Solvent: CC(=O)O
Product: Nc1cc(C2CCSCC2)nc2ccnn12
Temperature: 100 °C

Procedure:
A mixture of 3-aminopyrazole (19.3 mmol, 1.61 g) and 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (21.3 mmol, 3.60 g) in acetic acid (40 mL) was heated at 100° C. in a sealed tube overnight. After cooling to rt, all the volatiles were removed under reduced pressure to afford 5-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a light brownish oil. LCMS tR=0.59 Min. Mass calculated for, M+ 234.1, observed LC/MS m/z 235.1 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]=[CH:14]2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:1]([CH:8]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[NH:15][CH2:14]2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 2′-benzyl-5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL) and then sodium triacetoxy borohydride (206 mg, 0.97 mmol) was added followed by acetic acid (0.5 mL). The resulting mixture was stirred for 2 h at ambient temperature at which time it was quenched by the addition of saturated sodium bicarbonate solution. The mixture was diluted with EtOAc and then washed twice with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give tert-butyl 2′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate. The material thus obtained was used without further purification (185 mg, 92%). LCMS (APCI+) m/z 311.1; Rt=4.32 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=12.Cl.C([OH:27])C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=1[C:2]2=[O:27]
Reactant: CCO
Reactant: Cc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Agent: Cl
Product: Cc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.21 g, 6.68 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL, 36.0 mmol) was added and the mixture was heated under reflux for 3 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (2.08 g, 99% yield).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(O)C.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\NC(=O)c1ccncc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (168 mg, 0.73 mmol) was suspended in ethanol (4 ml) and water (1 ml). Isonicotinic hydrazide (110 mg, 0.80 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 24 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 136 mg (75%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(CC)COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(CC)CC)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-ethylbutoxy)benzonitrile (Example 22b) and ethyl 3-oxobutanoate as a white solid (89%). 1H NMR (400 MHz, DMSO-d6) δ 0.90 (t, J=8 Hz, 6H), 1.32 (t, J=8 Hz, 3H), 1.48-1.41 (m, 4H), 1.79-1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J=4 Hz, 2H), 4.31 (q, J=8 Hz, 2H), 6.92 (dd, J=2, 8 Hz, 1H), 7.23 (dd, J=2, 8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 8.04 (brs, 1H). MS 331 (MH+).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5][C:4]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].[OH:25]O>>[ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([S:9]([CH2:10][CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[O:25])[CH:6]=[CH:5][C:4]=1[NH:20][S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: OO
Reactant: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1NS(C)(=O)=O
Agent: Cl
Product: Cc1cc(S(=O)CCCN(C(C)C)C(C)C)ccc1NS(C)(=O)=O

Procedure:
React N-[2-methyl-4-[[3-[bis(1-methylethyl)amino]propyl]thio]phenyl]methanesulfonamide hydrochloride with 30% aqueous hydrogen peroxide in a manner similar to Example 8 to obtain the title compound.