Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[CH:102]=[N:103][N:104]([CH2:108][CH2:109][CH2:110][OH:111])[C:105]=2[C:106]#[N:107])=[CH:99][CH:100]=1>>[C:106]([C:105]1[N:104]([CH2:108][CH2:109][CH2:110][OH:111])[N:103]=[CH:102][C:101]=1[C:98]1[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:25]=2)=[CH:100][CH:99]=1)#[N:107]
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2C#N)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 55 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 218 mg, 0.480 mmol) and 3-amino-6-[5-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 53C, 151 mg, 0.504 mmol) to afford 191 mg of the title compound (55%). 1H NMR (400 MHz, CD3OD) δ 9.19 (br. s., 1H), 8.47 (s, 1H), 8.38 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.69 (br. s., 1H), 7.08 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 4.01-4.14 (m, 3H), 3.88 (s, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.36 (s, 2H), 2.99 (s, 3H), 2.17 (quin, J=6.5 Hz, 2H), 1.18-1.31 (m, 8H). MS (ESI): m/z=718.56 [M+H]+. UPLC: tR=1.36 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[N+]([C:13]1[C:14]([N+]([O-])=O)=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:18]1[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Aromatic nitro compounds like dinitrotoluene (DNT) or mononitrobenzene (MNB) are commercially produced through nitration of an aromatic with a mixture of nitric acid and sulfuric acid. The reaction is a biphasic reaction, typically the reaction rate is determined by the mass transfer between the two phases. In case of toluene nitration the reaction is typically carried out isothermally, toluene is present in molar substochiometry which means the molar ration of nitric acid to toluene is >1, typically 1.01-1.2. In a first step the toluene is nitrated to form mononitrotoluene (MNT). The biphasic reaction mixture undergoes phase separation into an aqueous phase containing the main part of sulfuric acid and an organic phase containing the main part of MNT. The organic phase then undergoes nitration to DNT in a further biphasic reaction. Again the reaction mixture undergoes phase separation into an aqueous phase and an organic phase containing DNT.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Br:15])=[CH:12][C:13]=1[I:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Br)cc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Br)cc1I
Yield: 98.1 %

Procedure:
(6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (13.6 g, 34.1 mmol) was dissolved in dichloromethane (150 mL) and trifluoroacetic acid (50 mL) was then added. The resultant solution was stirred at ambient temperature for 2 h then evaporated under reduced pressure. The resultant residue was treated with a saturated solution of sodium hydrogen carbonate and the resultant solid was treated with water (50 mL) then extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound as an off-white solid (10.0 g, 98%). 1H NMR (CDCl3, 300 MHz): 7.81 (s, 1H), 7.73 (s, 1H), 4.14 (s, 2H). LCMS (Method B): RT=3.03 min, M+H+=299/301.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)c2cccs2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.7 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and thiophenesulfonyl chloride (126 mg, 0.69 mmol) and the reaction mixture was stirred at ambient temperature for 4 d. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20) afforded the title compound (95 mg, 33%) as an orange solid. MS: m/e=495.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(N)c1N
Yield: 100.2 %

Procedure:
A solution of methyl 2-amino-4-methoxy-3-nitrobenzoate (1.84 g, Reference Example 9) in ethanol (100 ml) was treated with 10% palladium on carbon (0.2 g). The resulting suspension was stirred under 3 atmospheres of hydrogen for 3 hours. The catalyst was then removed by filtration and the filtrate evaporated to give the title compound 1.6 g) as a black solid which was used without further purification. M+196.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=O)[CH:17]=[CH:18][C:19]=1[Cl:20].[C:25]1([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH:34]([CH2:38][OH:39])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:33][CH:34]2[CH2:38][OH:39])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: OCC1CN(Cc2ccccc2)CCN1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1,1'-Carbonyldiimidazole (236 mg) was added to a stirred solution of 3,4-dichlorophenylacetic acid (314 mg) in dry dichloromethane (6 ml) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 1 h and added dropwise to a cooled solution of 4-(phenylmethyl)-2-piperazinemethanol (300 mg) in dry dichloromethane (3 ml) and stirred at room temperature for 19 h. The reaction mixture was diluted with dichloromethane (5 ml) and washed with 2N sodium carbonate solution (3×10 ml). The organic layer was dried and evaporated to give an oil which was purified by flash column chromatography using gradient elution with dichloromethane:ethyl acetate (2:1), dichloromethane:ethyl acetate (1:1) and dichloromethane:methanol (9:1) to give the title compound as a solid (200 mg). m.p. 148°-150°.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
2-Hydroxy-2-phenylethanamine (2.15 g) and 1-(4-carbomethoxyphenyl)propan-2-one (3.0 g) were heated in refluxing benzene (100 ml) under a Dean and Stark head until the theoretical amount of water had been collected. The solvent was replaced by methanol and the mixture was stirred and cooled during the portionwise addition of sodium borohydride (3.0 g). The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and chloroform. The organic extract was dried, evaporated and recrystallised from hexane, mp 82°-84°, (45:55 mixture of diastereoisomers) and from benzene/hexane, mp 121°-122°, (80:20 mixture of diastereoisomers). τ (CDCl3) 8.97 (3H, d, J=6 Hz), 6.85-7.60 (7H, m), 6.15 (3H, s), 5.33 (1H, m), 2.81 (2H, d, J=8 Hz), 2.70 (5H, m), 2.04 (2H, d, J=8 Hz). 13C NMR (d6DMSO)ppm. 20.15, 19.90; 53.82, 53.64; 55.03 54.86; 71.91, 71.73.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][CH:23]([F:31])[C:24]1[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:26]5[CH:25]=[C:24]([CH:23]([F:31])[F:22])[S:28][CH:27]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1csc(C(F)F)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)F)c4)cc3=O)cn12
Temperature: 100 °C
Yield: 51.6 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (100 mg), (5-(difluoromethyl)-3-thienyl)methanol (88 mg), potassium tert-butoxide (109 mg) and toluene (3 ml) was heated at 100° C. for 1 h. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (64.1 mg) as a white solid.
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Yield: 73 %

Procedure:
A solution of ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (0.50 g, 2.05 mmol), trimethyl orthoformate (0.25 mL, 2.28 mmol) and p-toluenesulfonic acid monohydrate (10 mg) in methanol (10 mL) was subjected to microwave irradiation for 10 minutes at 90° C. (30 psi). The solvent was removed in vacuo and the residue was suspended in dichloromethane. The solid was collected by filtration, washed with saturated sodium bicarbonate and water, and dried to afford the title compound in 73% yield (0.38 g): 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 4.32 (q J=6.9 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); MS (ES+) m/z 255.2 (M+1).
Reaction SMILES: [BH4-].[Na+].[Te].C(O)(=O)C.[CH3:8][O:9][C:10](=[O:26])[CH:11]=[C:12]1[S:24][C:15]2=[N:16][C:17]3[C:22]([CH2:23][N:14]2[C:13]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3>C(O)C>[CH3:8][O:9][C:10](=[O:26])[CH2:11][CH:12]1[S:24][C:15]2=[N:16][C:17]3[C:22]([CH2:23][N:14]2[C:13]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CC1SC2=Nc3ccccc3CN2C1=O
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
A suspension of sodium borohydride (3.03 g, 0.08 mol) and 4.38 g (0.034 mol) tellurium powder in 135 ml anhydrous ethanol was heated under nitrogen atmosphere for 15 min. After cooling to -20° C., 8.08 ml glacial acetic acid in 33.65 ml anhydrous ethanol was added dropwise, and the mixture was stirred at that temperature for 5 min, followed by the addition of 3.50 g (0.013 mol) of (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid methyl ester in 13.5 ml anhydrous ethanol. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. Then, the mixture was filtered through celite, and evaporated under reduced pressure. The residue was taken up in water and extracted with chloroform. The organic extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, yielding 1.16 g of 2,3-dihydro-3-oxo-5H-thiazolo[2,3-b]quinazoline-2-acetic acid methyl ester. Mp 143°-144° C. after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nnnn1-c1ccccc1
Product: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Temperature: 65 °C
Yield: 87 %

Procedure:
5-Chloro-1-phenyl-1H-tetrazole (500 g, 2.78 mol) was carefully added in one portion to stirred white fuming nitric acid (91.5% HNO3, 2.5 L). The internal temperature of the mixture increased steadily to 65° C. then fell. An aliquot was removed and partitioned between water and dichloromethane. TLC analysis (80:20 hexanes/ethyl acetate) indicated consumption of starting material. The mixture was carefully poured into stirred ice (3 L), water (2 L) and dichloromethane (2 L). The layers were separated and the aqueous was extracted with dichloromethane (2 L). The combined organic phase was washed with 5% aqueous sodium bicarbonate solution (1 L), dried (MgSO4), filtered, and concentrated to a solid. The solid was mixed with 90:10 hexanes/ethyl acetate (3 L) and heated to 65° C. The mixture was cooled overnight (2-5° C.). Filtration afforded a white crystalline solid (544 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 8.51 (d, 9.5 Hz, 2H), 7.91 (d, 8.8 Hz, 2H); mp 96.5° C.; Rf=0.2 (K).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:7])=[O:6].[NH3:11]>[OH-].[NH4+]>[NH2:11][C:3]([C:2]([F:10])([F:9])[F:1])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: N
Reactant: C/C(=C/C(=O)O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: CC(N)(CC(=O)O)C(F)(F)F

Procedure:
A solution of 3-trifluoromethylcrotonic acid (10 g) and liquid ammonia (23 ml) in ammonium hydroxide (27 ml sd=0.88) was heated in a closed steel vessel at 148°-152° C. for 16 hours evaporation of the cooled solution gave 3-amino-3-trifluoromethylbutyric acid (10.2 g), as a viscous colourless oil. ##STR6##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[SH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][S:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CCOC(=O)c1ccc(S)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(SCCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a stirred solution of 5.6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 4.2 parts of ethyl 4-mercaptobenzoate and 6 parts of triphenylposphine in 135 parts of tetrahydrofuran was added dropwise a solution of 4 parts of diethyl diazenedicarboxylate in 45 parts of tetrahydrofuran at 20° C. Upon complete addition, stirring was continued overnight at this temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was ectracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.3 parts (13.5%) of ethyl 4-[[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propyl]thio]benzoate; mp. 96.3° C. (comp. 164).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([N:35](C)[C:36](=O)OC(C)(C)C)[CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:45]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([NH:35][CH3:36])[CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12]2)[C:3]1=[O:45]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)N[C@@H](CCc2ccccc2)C(=O)N2CCC(N3C(=O)C(C)(C)c4ccccc43)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CCN(C(=O)N[C@@H](CCc2ccccc2)C(=O)N2CCC(N3C(=O)C(C)(C)c4ccccc43)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of tert-butyl (S)-1-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamoyl)pyrrolidin-3-yl(methyl)carbamate (267 mg, 0.42 mmol, EXAMPLE 47: Alternative Method, Step 1) in dichloromethane-trifluoroacetic acid (1:1, 6 mL) was stirred at room temperature for 1 h. The mixture was concentrated, diluted with dichloromethane, and washed with saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual oil was purified by preparative HPLC (32-96% methanol in 0.01% ammonia aqueous solution) and by amino gel column chromatography to give the title compound (209 mg, 93%) as a colorless oil.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:12][CH:13]1[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[CH:16]=[CH:15][CH2:14]1.C(NC(C)C)(C)C>C(Cl)Cl>[Br:1][C:16]1[C:17]([OH:23])=[C:18]([C:13]([CH3:12])=[CH:14][CH:15]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1C(=O)C=CCC1C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)c1c(C)ccc(Br)c1O

Procedure:
A solution of 1,3-dibromo-5,5-dimethylhydantoin (65 g) in DCM (150 mL) was added dropwise to a stirred and cooled solution of methyl 6-methyl-2-oxocyclohex-3-enecarboxylate (prepared in a similar manner to Hauser et al, Synthesis 1980 814, 75.16 g) and N,N-di-isopropylamine (6.15 mL) in DCM (500 mL) at 0° C. and the resultant mixture was stirred at room temperature for 3 days. The mixture was recooled to 0° C. and further 1,3-dibromo-5,5-dimethylhydantoin (11 g) was added and the mixture was stirred at 0° C. for 3 hours. The precipitate was removed by filtration and the filtrate was evaporated to dryness to give methyl 3-bromo-2-hydroxy-6-methylbenzoate (114.5 g) as an oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Yield: 78.5 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-azido-1-phenyl-ethyl)-amide (120 mg, 0.27 mmol), 5% Pd/C (cat) in methanol (5 mL) was subjected to an atmosphere of hydrogen (balloon). After completion the solution was filtered and concentrated in vacuo. The residue was purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (80 mg, 75%) (ESI) 378 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 8.00 (1H, d, J=5.47 Hz) 7.82 (1H, d, J=5.42 Hz) 7.45 (1H, d, J=5.42 Hz) 7.25-7.35 (5H, m) 7.16-7.24 (1H, m) 6.75 (1H, d, J=5.47 Hz) 6.39 (1H, d, J=3.12 Hz) 4.97 (1H, dd, J=8.03, 5.34 Hz) 2.85-2.94 (1H, m) 2.77-2.85 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[Cl:1][C:2]1[N+:7]([O-:27])=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Cl)nnc1Oc1c(C)cccc1C
Solvent: ClCCl
Product: COc1cc(Cl)[n+]([O-])nc1Oc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 384 h
Yield: 56.8 %

Procedure:
3.42 g (12.9 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine, dichloromethane (110 mL) and 3.34 g (15.4 mmol) of 80% m-chloroperbenzoic acid were mixed, and the mixture was stirred at at room temperature for 16 days. The reaction mixture was poured into ice-cold saturated aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.06 g (7.33 mmol, Yield: 56.8%) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide.