Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1=[O:6])[CH:2]=[CH2:3]>C(O)C.[Pd]>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: C=CCn1c(=O)c2[nH]c(C)nc2n(CCCC)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCn1c(=O)n(CCC)c(=O)c2[nH]c(C)nc21
Yield: 99.2 %

Procedure:
5 g of 1-allyl-3-butyl-8-methyl xanthine (Example 1) are dissolved in 100 ml of ethanol in a hydrogenation apparatus, followed by the addition of 500 mg of Pd (10%)/C. Hydrogenation is carried out at ambient temperature until the consumption of hydrogen is over (approximately 1 hour). The mixture is filtered under heat, the precipitate is washed with ethanol and the solvent is evaporated from the filtrate, leaving 5 g of colourless crystals which are recrystallised from methanol. Mp: 174°-175° C. C-NMR (Table 2).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O>C1COCC1>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:13][O:12][CH2:11][CH2:10][Si:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A stirred suspension of 1.2 grams of 60% sodium hydride (0.03 mole-in mineral oil) in 25 mL of THF was cooled to 0° C. to 5° C., and a solution of 2.0 grams (0.03 mole) of imidazole in 30 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for an additional 15 minutes, then a solution of 4.7 grams (0.03 mole) of 2-(trimethylsilyl)ethoxymethyl chloride in 10 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred during an 18 hour period. After this time, the reaction mixture was stirred with 50 mL of water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and was then dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residual oil. The residue was distilled under reduced pressure, yielding 3.8 grams of the subject compound; bp 71° C./0.1 torr. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][BH:24][O:23]1.C([O-])(=O)C.[K+]>COCCOC.Cl[Pd]Cl>[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[O:23]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3cncnc32)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cncnc32)cc1

Procedure:
As shown in FIG. 1—step iv, a mixture of compound 1004 (140 mg, 0.40 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane dimer (121 mg, 0.477 mmol), PdCl2 dppf2 (16 mg, 0.02 mmol) and potassium acetate (117 mg, 1.19 mmol) in 2 mL of DME were microwaved at 150° C. for 10 minutes. The reaction mixture was filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, 158 mg (98%) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, compound 1005: ESMS M+1=317.07.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[S:13][C:6]=12.S(Cl)([Cl:31])=O>>[Cl:31][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)=[N:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CO)cn4)sc23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of 101 (2.23 g, 5.61 mmol) in thionyl chloride (8.14 mL) under nitrogen was stirred at RT overnight. The reaction mixture was cooled down to 0° C., and ice was added. The resultant suspension was stirred for 1 h, the solid was collected by filtration, rinsed with water and dried under high vacuum to afford the title compound 102 (2.06 g, 4.96 mmol, 88% yield) as a yellow fluffy solid which was used in the next step without any further purification. MS (m/z): 416.4 and 418.4 (M+H).
Reaction SMILES: [Br-:1].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH3:25].CO>>[BrH:2].[Br-:1].[NH2:25][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CO
Product: Br
Product: NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Yield: 41 %

Procedure:
(3-bromopropyl)(triphenyl)phosphonium bromide (4.9 g, 10.0 mmol) was treated with 7 M ammonia in methanol (97 mL, 680 mmol) in a sealed tube. The mixture was heated at 85° C. for 4 hours and cooled to room temperature. The volatiles were removed, and the resultant semi-solid was purified on a silica gel column eluting with first with 20% methanol in methylene chloride followed by 25% 1 M ammonia in methanol and methylene chloride to give the title compound (2.07 g) in a 41% yield.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:27])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[C:18]=2[CH3:26])=[N:13]1>>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH3:27])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1cocn1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cocn3)n2)ccc(C#N)c1Cl
Yield: 0.81 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.181 g, 1.596 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.430 g, 1.330 mmol). The product was purified by Flash-chromatography. Yield 0.813%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.57 (s, 3H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.44 (d, 1H), 7.50 (d, 1H), 7.51-7.55 (m, 2H), 7.60 (dd, 1H), 7.85 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>C1COCC1.C(Cl)Cl>[OH:35][CH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methylidene-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexane (Example 165, 117 mg, 0.35 mmol) was added 9-BBN (7 mL, 0.5 N, 3.5 mmol) in THF. The reaction mixture was stirred at rt for 1 h, and then heated to 45° C. for 3 h. To the solution was then added NaOH (3 mL, 10%) and H2O2 (4 mL, 30%) and the mixture was heated at 45° C. for 14 h. The reaction mixture was poured into CH2Cl2 and washed with 2N HCl and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, EtOAc/hexane, 2:1) to give the title compound as a 2:1 mixture of two diastereomers.
Reaction SMILES: [OH:1]C1C=CC=CC=1C=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][C:20]1[CH:21]=[CH:22][C:17]([CH:23]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccccc1
Reactant: Nc1ccccc1
Product: Oc1ccc(C=Nc2ccccc2)cc1
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of hydroxy benzaldehyde (5.00 g, 41 mmol) in toluene (200 cm3) was heated to 109° C. before aniline (1.86 g, 20 mmol) was added under nitrogen. The mixture was then allowed to cool, forming a yellow solid after 30 minutes. The reaction was continued with the further addition of aniline (1.86 g, 20 mmol). Dean and Stark apparatus was used to collect water (0.6 cm3). Reflux continued for a further 5 hours by which time 0.7 cm3 of water had collected. After cooling the mixture, a thick crystalline mass was formed which was filtered and dried under vacuum at 90° C. to give 4-hydroxybenzylidene-aniline (7.3 g, 94%) as pale cream crystals.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH:26]=O>CO>[CH:1]1([CH2:4][N:5]2[C:10]([NH:11][N:12]=[CH:26][C:19]3[C:18]4[C:23](=[CH:24][CH:25]=[C:16]([Cl:15])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[CH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:2][CH2:3]1
Reactant: NNc1cc(=O)[nH]c(=O)n1CC1CC1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Solvent: CO
Product: O=c1cc(NN=Cc2ccnc3ccc(Cl)cc23)n(CC2CC2)c(=O)[nH]1
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a suspension of 1-cyclopropylmethyl-6-hydrazinopyrimidine-2,4[1H,3H]dione (5.05 g) in methanol (75 mL) was added 6-chloroquinoline 4-carbaldehyde (5.30 g). After stirring overnight, the reaction was filtered, yielding a yellow solid (10 g).
Reaction SMILES: B(Br)(Br)Br.C([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([NH2:21])=[C:14]([O:19]C)[CH:15]=2)[CH2:10]1)(=O)C.CO.C(Cl)[Cl:25]>>[ClH:25].[ClH:25].[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([NH2:21])=[C:14]([OH:19])[CH:15]=2)[CH2:10]1
Reactant: COc1cc2c(cc1N)CC(NC(C)=O)CC2
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: CO
Product: Cl
Product: Nc1cc2c(cc1O)CCC(N)C2

Procedure:
2.7 ml of boron tribromide are added to a solution of 23 g of 2-acetamido-7-amino-6-methoxy-1,2,3,4-tetrahydronaphthalene in methylene chloride at -60° C. The mixture is left to return to ambient temperature, cooled to -60° C. and neutralised with methanol. After evaporation to dryness, 12 N hydrochloric acid is added and the mixture is heated under reflux for 48 hours. It is then left to cool and the crystals formed are filtered off, washed with acetone and then with diethyl ether and dried. The product collected melts above 300° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23](=[O:28])[N:22](CC2C=CC(OC)=CC=2)[CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:27][C:26]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][NH:22][C:23]2=[O:28])=[CH:18][C:17]=1[S:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: COc1ccc(Cn2ccc3cc(S(=O)(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2cc(S(=O)(=O)C3CCNCC3)c(Cl)cc12
Temperature: 150 °C
Yield: 51.1 %

Procedure:
190 mg 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-6-sulfonyl]-piperidine-1-carboxylic acid tert-butyl ester (287) were dissolved in 2 ml of TFA and heated in a microwave at 150° C. for 50 min in total. After evaporation the mixture was dissolved in 1 N HCl and extracted with dichloromethane and lyophilized. 58 mg of 7-Chloro-6-(piperidine-4-sulfonyl)-2H-isoquinolin-1-one could be obtained as the hydrochloride. Rt=0.81 min (Method B). Detected mass: 327.1/329.1 (M+H+).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Cl:25][C:26]1[C:27]([O:35][CH2:36][C:37]23[CH2:47][C:41]4([F:48])[CH2:42][C:43]([F:46])([CH2:45][C:39]([F:49])([CH2:40]4)[CH2:38]2)[CH2:44]3)=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31]([OH:33])=O.COC[CH2:53][S:54]([NH2:57])(=[O:56])=[O:55].CS(N)(=O)=O>>[Cl:25][C:26]1[C:27]([O:35][CH2:36][C:37]23[CH2:38][C:39]4([F:49])[CH2:45][C:43]([F:46])([CH2:42][C:41]([F:48])([CH2:40]4)[CH2:47]2)[CH2:44]3)=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:33]
Reactant: O=C(O)c1cnc(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)c(Cl)c1
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cnc(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-chloro-6-((3,5,7-trifluoroadamantan-1-yl)methoxy)nicotinic acid and to replace 2-methoxyethane- sulfonamide with methyl sulfonamide. Purification by reverse phase HPLC, the title compound was obtained as a colorless solid (0.13 g, 18%): 1H NMR (300 MHz, DMSO-d6) δ 12.24 (br s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 4.29 (s, 2H), 3.33 (s, 3H), 2.24-2.14 (m, 3H), 2.06-1.96 (m, 3H), 1.81-1.74 (m, 6H); MS (ES−) m/z 451.2, 453.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][OH:17])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1.CN1[C:30]2[CH:31]=[CH:32][C:33](Cl)=[CH:34][C:29]=2[C:28](C2C=CC=CC=2)=NCC1=O.C(Cl)(=O)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:17][N:16]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CNC(=O)c1nc(-c2cccc(C(=N)NO)c2)cnc1N
Solvent: CCOC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(-c3noc(-c4ccccc4)n3)c2)cnc1N
Reaction time: 1 h
Yield: 19.9 %

Procedure:
3-Amino-N-methyl-6-{3-[(hydroxyamino)(imino)methyl]phenyl}pyrazine-2-carboxamide (40 mg, 0.14 mmol) was suspended in DMF (750 uL) followed by addition of PL-DIPAM (diisopropylaminomethyl) resin (100 mg, 2.33 mmol/g) and benzoyl chloride (20 uL, 0.17 mmol). The mixture was agitated for one hour then diluted with ethyl acetate and the spent resin removed by filtration, The organic filtrate was washed with water (3×), brine then dried over anhydrous magnesium sulfate. The mixture was then filtered and concentrated and the solid residue suspended in TIF (1 mmol) followed by addition of tetra-N-butylammonium fluoride (TBAF) (1.0 M in THF, 100 uL) and the solution was allowed to stir at room temperature over 12 hours. The mixture was concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed with water (1×), 1.0 M aqueous hydrochloric acid (lx) then brine and dried over anhydrous magnesium sulfate. The material was filtered and concentrated then the residue purified by preparative reverse phase HPLC (water/acetonitrile/0.1% TFA eluent). The pure fractions were combined and lyophilized to afford 3-amino-N-methyl-6-[3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]pyrazine-2-carboxamide (10.4 mg, 20% yield) as a yellow solid: MS (EI) for C20H17N6O2: 372 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=O)=[CH:4][CH:3]=1.[NH3:12]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1ccc(Cl)nn1
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99 %

Procedure:
Dissolve methyl 6-chloropyridazine-3-carboxylate (0.498 g, 2.89 mmol) in methanol (28 mL). Cool the solution to 0° C. with an acetone/dry ice bath. Bubble ammonia into the reaction mixture then allow it to warm to 0° C. over 1 hour before concentrating to give the title compound (0.451 g, 99%): TOF MS ES+ 157.0 (M)+, HRMS calcd for C5H4N3OCl 157.0043 (M)+, found 157.0010, time 4.45 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1 TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min then 20-95% over 18], tR=5.2 min, 100% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)Nc1cc(Br)sc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.309 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 15 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (240 mg) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:24][C:23]2=[O:36]>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[O:26][CH:25]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][C:23]3=[O:36])=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)C(=O)CC(c2ccccc2)O3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 6-hydroxyflavone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: N[C:2]1[C:6]([CH2:7][C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]([NH:21][C:22](=[N:25][C:26]([O:28][CH3:29])=[O:27])SC)([O:19][CH3:20])=[O:18].C([N:32](CC)CC)C>CN(C)C=O>[C:26]([N:25]([C:2]1[C:6]([CH2:7][C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[C:22]([NH:21][C:17]([O:19][CH3:20])=[O:18])=[NH:32])([O:28][CH3:29])=[O:27]
Reactant: CCN(CC)CC
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COC(=O)c1[nH]cc(Cc2ccsc2)c1N
Solvent: CN(C)C=O
Product: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2ccsc2)c[nH]c1C(=O)OC
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Methyl 3-amino-4-(3-thienylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 14 (11.8 g, 0.05 mol), N,N′-bis-carbomethoxy-S-methylisothiourea (11.3 g, 0.055 mol) and triethylamine were stirred together in dimethyl formamide (100 mL) and cooled to 5° C. Mercuric chloride (14.9 g, 0.055 mol) was added and an immediate precipitate was observed. The mixture was stirred at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[F:1][C:2]1[C:3]([I:11])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cnc2[nH]ccc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(I)c(F)cnc21
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 0.019 mol) in DMF (30.0 mL) cooled at 0° C. under nitrogen was portionwise added sodium hydride (1.13 g, 0.0282 mol). The reaction was stirred for 1 hour. To the mixture was slowly added [β-(trimethylsilyl)ethoxy]methyl chloride (4.05 mL, 0.0229 mol). The reaction was stirred at 0° C. for 1 hour and quenched with water. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-25% EtOAc/hexanes to afford 7.1 g (95%) of 5-fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a yellowish oil. LC/MS found: 393.0 (M+H)+.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6](#[N:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][C:6]#[N:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=CC#N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC#N
Temperature: 100 °C
Yield: 82.9 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. The reaction mixture is heated to 100° C. and 371 g (7 mol) of acrylonitrile and 500 g of a 5% sodium peroxodisulfate solution (1.5 mol % based on acrylonitrile) are added dropwise at atmospheric pressure. Then, the water is distilled off, and the residue is taken up in THF, extracted and filtered. The solvent of the filtrate is removed in vacuo to leave 732 g (83% of theory) of ethyl(2-cyanoethyl)phosphinic acid as oil.