Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:24]3[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=3)[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([C:31]#[N:32])[CH:38]=4)=[CH:26][CH:25]=3)[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=S(=O)(NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(-c2ccc(C3(CNS(=O)(=O)c4ccc(F)c(Cl)c4)CCN(CC4CC4)CC3)cc2)c1
Temperature: 25 °C
Yield: 450.7 %

Procedure:
To a flask containing 3-chloro-N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-4-fluorobenzenesulfonamide (0.047 g, 0.04 mmol) was added Pd(PPh3)4 (0.005 g, 0.004 mmol, 10 mol %), 3-cyanophenylboronic acid (0.01 g, 0.06 mmol, 1.5 eq.) and Na2CO3 (0.106 g, 1 mmol). The mixture was suspended in toluene (1.5 mL), EtOH (0.75 mL) and H2O (0.5 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid which was purified by HPLC to give 3-chloro-N-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-4-fluoro-benzenesulfonamide (0.097 g, 45%). MS (ESI): 538.2/540.2.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2)(281 mg, 1.0 mmol) according to general procedure II. Obtained as a light-brown solid (200 mg, 35%). MS (ISP) 566.2 [(M+H)+]; mp 200-201° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]CC4C=CC=CC=4)=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:3]1.[H][H].C1COCC1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 12 h

Procedure:
A solution of 2.50 g (4.38 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure for 4.5 h. To complete the reaction a further 250 mg of catalyst were added, the mixture was hydrogenated for 12 h at 40° C., combined with 25 mL THF and 250 mg catalyst and hydrogenated for a further 12 h at 40° C. The catalyst was removed by suction filtering and the filtrate was concentrated by evaporation i. vac. The residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([C:13](=O)[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[BH3-]C#[N:20].[Na+]>CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([CH:13]([NH2:20])[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1ncc(Oc2ccc(F)cc2)cn1
Yield: 94.3 %

Procedure:
1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH3CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.26 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:34][CH3:35])([O:32][CH3:33])[CH2:30][F:31])[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:32][CH3:33])([O:34][CH3:35])[CH2:30][F:31])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COC(CF)(OC)c1cccc(Br)n1
Product: COC(CF)(OC)c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared in the same manner described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-bromo-6-(2-fluoro-1,1-dimethoxyethyl)pyridine (85 mg, 0.32 mmol) as starting materials.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.ClC([O:24][C:25](Cl)=[O:26])(Cl)Cl.[O:28]1[CH2:33]COCC1>>[N:8]1([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:33]([N:5]3[CH2:10][CH2:9][N:8]([CH2:11][C:25]([OH:24])=[O:26])[CH2:7][CH2:6]3)=[O:28])=[CH:16][CH:17]=2)[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]1
Reactant: C1COCCO1
Reactant: Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(O)CN1CCN(C(=O)Nc2ccc(N3CCNCC3)cc2)CC1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4-[4-(trifluoroacetyl)-1-piperazinyl]aniline 4 (250 mg, 0.9 mmole) was dissolved in dioxane (5 ml) and TEA (125(1, 0.9 mmole). Trichloromethylchloroformate (110(1, 0.9 mmole) was added dropwise via syringe. Solid precipitated out upon addition, mixture stirred 30 min and was filtered to yield the title compound as a white solid (10 mg, 37%). MS (ES) m/e 300.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][CH:50]1[NH:54][CH2:53][C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])([OH:55])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:54]3[CH:50]([CH3:49])[CH2:51][C:52]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[CH3:62])([OH:55])[CH2:53]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: Cc1ccccc1C1(O)CNC(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3C)CC2C)cc1Cl
Yield: 29.3 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-(2-methylphenyl)pyrrolidin-3-ol (8 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z: calcd for C23H23ClN2O4: 426.1346, found 426.1350.
Reaction SMILES: Cl.C=[O:3].[C:4]1([P:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O-])(O)=[O:19].[Na+]>>[OH:19][CH2:18][P:10](=[O:3])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Product: O=P(CO)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Hydroxymethyl diphenylphosphine oxide was prepared according to Lawrence & Jackson [J. Chem. Soc., Perkin Trans. 2002, 1, 2260]. To a mixture of HCl (18.9 ml) and aqueous formaldehyde (18.9 ml, 37 wt %) was added diphenyl chlorophosphine (2.80 ml, 10.6 mmol). The reaction mixture was heated to 100° C. for 18 hours under a nitrogen atmosphere. The reaction was neutralized with aqueous NaHCO3, and the aqueous phase was extracted with CH2Cl2 (3×30 ml). The organic phase was dried with anhydrous Na2SO4. Hydroxymethyl diphenylphosphine oxide (2.907 g, 89% yield) was obtained after evaporation of the solvent as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].C[O-].[Na+].[NH3:18]>CO>[NH:14]=[C:13]1[C:12]2[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=2[C:1](=[NH:18])[NH:2]1
Reactant: N
Reactant: N#Cc1cc2ccccc2cc1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C1NC(=N)c2cc3ccccc3cc21
Yield: 66 %

Procedure:
In 2.5 moles of 2,3-dicyanonaphthalene, 0.075 mole of sodium methoxide and 1 liter of methanol, an ammonia gas was flowed with a suitable flow rate for 40 minutes. Then, the reaction solution was refluxed with heating while flowing the ammonia gas for 4 hours. After cooling, the product was filtered, and recrystallized from a mixed solvent of methanol/ether to yield yellow 1,3-diiminobenz (f) isoindoline in 66% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CN(C=O)C.CCOCC.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([Br:32])=[CH:34][CH:35]=2)[CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccc(Br)cc3)CC2C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 0.30 g (0.820 mmol) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (Step 1, Example 220) in 10 mL of DMF was added 0.339 g (2.459 mmol) of potassium carbonate followed by 0.205 g (0.820 mmol) of p-bromobenzyl bromide. The reaction was stirred at room temperature for 15 h, then diluted with ether and water. The organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.438 g of 4-(4-bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester as a colorless oil. Electrospray Mass Spec 534.9, 536.8 (M+H)+
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:46][CH2:47][CH2:48][CH3:49])[C@H:32]([OH:45])[C:33]([NH:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:46][CH2:47][CH2:48][CH3:49])[C:32](=[O:45])[C:33]([NH:35][C@H:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)N[C@@H](CC)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
0.383 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one was added to a solution of 0.285 g of 3(S)-(tert-butoxyformamido)-2(S)-hydroxy-N-(1(S)-phenylpropyl)heptanamide in 20 ml of dichloromethane. The mixture was stirred at room temperature for 30 minutes and then a further 30 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one were added. The mixture was stirred at room temperature for 30 minutes and then diluted with ethyl acetate. The solution was extracted with a solution of 10 g of sodium thiosulphate in 40 ml of saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica gel using 20% ethyl acetate in hexane for the elution to give 200 mg of 3(S)-(tert-butoxyformamido)-2-oxo-N-(1(S)-phenylpropyl)heptanamide, MS: m/e 377.1 [M+H]+.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[NH:27][NH2:28].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:28][NH:27][C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
i. A mixture of 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-chloro-pyridazine, t-butyl carbazate and 1,8-bis-(dimethylamino)naphthalene was heated for 2 hours to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](SC)=[N:8]2)=[CH:4][N:3]=1.[S:13]([O-:18])(O[O-])(=O)=[O:14].[K+].[K+].[CH3:21]C#N.O>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([S:13]([CH3:21])(=[O:18])=[O:14])=[N:8]2)=[CH:4][N:3]=1
Reactant: CC#N
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1nc2nc(Cl)ncc2[nH]1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc2nc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirring solution of 2-chloro-8-(methylthio)-7H-purine (700.0 mg, 3.49 mmol) in 50% CH3CN/water (44.8 mL) was added potassium peroxymonosulfate (oxone, 4.72 g, 7.68 mmol). The reaction was stirred under N2 at RT for 17 h, then filtered and the filtrate was added to a stirring EtOAc (1 L)/water (0.56 L) mixture. The aqueous layer was separated and back-extracted with EtOAc (0.2 L). The combined organic layers were evaporated under reduced pressure to afford the title compound. LC-MS: calculated for C6H5ClN4O2S 231.98 observed m/e: 233.11 (M+H)+ (Rt 0.58/2.0 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18](=[S:20])[NH2:19])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]3[S:20][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[N:19]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1-c1ccccc1F
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide (820 mg, 2.8 mmol) obtained in Example 30-B(vi) and ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (3.1 g, 13 mmol) obtained in Example 22-B(i) in 2-propanol (50 mL) was stirred at 90° C. for 7 h. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The solid was washed with EtOAc and diisopropyl ether, and dried to give the title compound (1.0 g, 75%) as a yellow solid.
Reaction SMILES: ClCCl.CS(C)=O.C(N(C(C)C)CC)(C)C.[OH:17][C@@H:18]([C@@H:29]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:36])[CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:20]>CS(C)=O>[O:20]=[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[C:18](=[O:17])[C@@H:29]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:36])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Under argon gas stream, to 10 ml of an anhydrous dimethylsulfoxide-dichloromethane (1:1) solution containing 1.38 g (8.6 mmol) of sulfur trioxide pyridine complex salt were successively added dropwise at 0° C. 1.47 ml (8.6 mmol) of diisopropylethylamine, and then, 5 ml of an anhydrous dimethylsulfoxide solution containing 350 mg (0.7 mmol) of (2S)-N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-(phenylmethoxycarbonyl)pyrrolidine-2-carboxamide, and the resulting mixture was stirred at the same temperature for 5 hours. After completion of the reaction, to the reaction mixture was added 25 ml of ice-water, and the resulting mixture was extracted with 30 ml of ethylacetate three times. The organic layers were combined, washed with 100 ml of a 10%-aqueous citric acid solution, 100 ml of a saturated aqueous sodium hydrogen carbonate solution, and then, 100 ml of a saturated NaCl solution, dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to obtain 300 mg (Yield: 86.1%) of the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][SiH:22]([O:25][CH3:26])[O:23][CH3:24]>[Pt].C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][Si:22]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOc1cccc(OC(=O)c2ccccc2)c1
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1cccc(OC(=O)c2ccccc2)c1)(OC)OC
Temperature: 20 °C

Procedure:
A mixture of 25.4 g. (0.1 mole) of 3-allyloxyphenyl benzoate, 50 mol. of dry toluene, 20 g. (0.15 mole) of trimethoxysilane and 2 drops of platinum hydrosilation catalyst is heated at 90° C. for 17 hours under nitrogen. After the reaction mixture is cooled to about 20° C., it is concentrated under reduced pressure to produce the uv precursor product. For purification, the product is passed through a short silica column using dichloromethane as an eluent.
Reaction SMILES: [CH2:1]1[C:4]2([CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.[C:17]([C:19]1([C:22](O)=[O:23])[CH2:21][CH2:20]1)#[N:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:17]([C:19]1([C:22]([N:6]2[CH2:7][CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:4]3([CH2:1][CH2:2][CH2:3]3)[CH2:5]2)=[O:23])[CH2:21][CH2:20]1)#[N:18]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)NC1CNCC12CCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C2(C#N)CC2)CC12CCC2
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (from Step 1 of Example 318, 0.177 g, 0.783 mmol), 1-cyanocyclopropanecarboxylic acid (0.104 g, 0.939 mmol), EDC (0.300 g, 1.565 mmol), HOBT (0.144 g, 0.939 mmol), and Hunig's Base (0.547 mL, 3.13 mmol) in DMA (7.67 mL) was stirred @ r. t. under N2 for 16 hrs. +/−MS analysis after 16 hrs indicated that the reaction had proceeded essentially to completion and no starting material was detected. The volatiles were removed under high vacuum. EtOAc, THF, and 10% aq LiCl solution were added. The layers were separated, the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine, dried over Na2SO4, and concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane:EtOAc yielded 0.191 g of the title compound as a pale yellow solid. +/−MS: m/e 320.3 (M+H). 318.5 (M−H), 220.2 (M+H-Boc), 264.2 (M+H-isobutylene). This material was used in the next step without further purification.