Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH4+].[C:11](=[S:14])([S-:13])[NH2:12]>CCO.CCOC(C)=O>[SH:14][C:11]1[S:13][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:12]=1
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)C(=O)CBr
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(S)n1
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of ethyl 3-bromo-2-oxopropanoate (200 mg, 1.02 mmol) in EtOH (5.0 mL) was added dithiocarbamic acid ammonium salt (96 mg, 1.23 mmol) The reaction mixture was stirred for 16 h, then diluted with EtOAc and washed with H2O and brine. The organic fraction was dried (MgSO4), filtered, and concentrated. Purification by preparative TLC afforded the title compound (45.0 mg, 23%). 1H NMR (DMSO-d6) δ=1.23 (t, 3H), 4.23 (q, 2H), 7.78 (s, 1H); ESIMS: m/z 188 (M+H). mp=120-121° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].[CH2:21]([O:27][C:28](Cl)=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([O:27][C:28]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Product: CCCCCCOC(=O)N1CCCc2cc(OCCCCN(CC)CC)ccc21

Procedure:
In analogy to example 3.9, Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and hexylchloroformate were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester as colorless oil, MS: 405 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCO)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
14.7 g (60.3 mmols) of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline, 90 ml of chloroform, 10.68 ml (2.0-fold equivalent weight) of 3,4-dihydro-2H-pyran and 0.76 g (0.05-fold equivalent weight) of pyridine p-toluenesulfonate were mixed, and the mixture obtained was heated at 70° C. for 1.5 hours in an atmosphere of argon. Thereafter, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution obtained, which was then extracted with chloroform (200 ml×2). The organic layer thus formed was washed with a saturated aqueous sodium hydrogencarbonate solution, which was then dried with anhydrous magnesium sulfate and thereafter concentrated. The residue thus obtained was purified by silica gel column chromatography (developing system: chloroform) to obtain 18.90 g of N-ethyl-N-[2-(tetrahydropyran-2-yl)oxyethyl]-4-bromoaniline (yield: quantitative; a colorless oily liquid).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][NH:14][C:15](=[O:20])[C@@H:16](Cl)[CH2:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([O:10][CH2:11][C@H:12]1[CH2:13][NH:14][C:15](=[O:20])[C@@H:16]([CH2:17][CH3:18])[O:21]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](Cl)C(=O)NC[C@@H](O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H]1O[C@@H](COCc2ccccc2)CNC1=O
Temperature: 0 °C
Yield: 99.2 %

Procedure:
To stirred suspension of sodium hydride (203.1 mg, 5.1 mmol as a 60% oil dispersion) in THF (18 mL) cooled to 0° C. was added dropwise (S)—N—((R)-3-(benzyloxy)-2-hydroxypropyl)-2-chlorobutanamide (362.8 mg, 1.270 mmol) in THF (3.8 mL) over a 5-min period after which the reaction was stirred at 0° C. for 30 min followed by stirring at rt for 5 h. The completed reaction was quenched with the slow addition of IPA (1 mL) followed by adding Dowex 50, H+ form, until a neutral to acidic pH was observed. The final suspension was filtered and the solid was rinsed two times with EtOAc. The combined filtrated were concentrated and the resultant crude product was purified over silica gel (Biotage, eluting with 1:1 EtOAc:heptane). The desired fractions were combined, concentrated and dried in vacuo to provide (2R,6R)-6-((benzyloxy)methyl)-2-ethylmorpholin-3-one (314 mg, 1.260 mmol, 99.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([I:22])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 dissolved in THF at −78° C. was added 1.6M solution of n-butyllithium in hexanes). The reaction mixture was stirred at −78° C. for 30 minutes. A solution of iodine in THF was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 45 minutes. The reaction mixture was quenched with saturated aq. Na2S2O3, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][C:18](=[O:21])[NH:19][OH:20])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[I:28]C1C=CC(OC2C=CC(S(N(CC(O)=O)CC(O)=O)(=O)=O)=CC=2)=CC=1>>[I:28][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][C:18](=[O:21])[NH:19][OH:20])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1

Procedure:
Compound 6e was prepared following the procedure described for 6b with reagent quantities adapted to the amount of starting material 5e (500 mg, 1.02 mmol). Yield: 305 mg, 0.60 mmol, 59%. 1H NMR (D2O): δ 7.72 (d, 3J=8.2 Hz, 2H, ArH), 7.52 (d, 3J=8.8 Hz, 2H, ArH), 7.03 (d, 3J=8.8 Hz, 2H, ArH), 4.01 (s, 4H, CH2COOH). ESI-MS calcd for C16H15IN2O7S 505.97 [M-H]−, obsd 507.0.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].[NH3:13]>>[Cl:11][C:4]1[C:3]([CH3:12])=[C:2]([NH2:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1N
Temperature: 130 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A suspension of 2,6-dichloro-3-nitrotoluene (6.0 g, 29 mmol) in 50% methanolic ammonia (60 mL) was stirred at 130° C. (340 lb pressure) for 18 hours. The autoclave was cooled to -30° C., opened, and the precipitate was filtered off and washed with methanol to give 4.14 g (76%) of 3-chloro-2-methyl-6-nitrobenzenamine.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:21](N)[CH2:22][CH2:23]C.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(O)C.O>[CH2:20]([N:2]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCn1cc(C(=O)OCC)c(=O)c2cc(I)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A suspension of (Z)-ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (WO2006/010733, 415 mg, 1.06 mmol) in ethanol (6 mL) at room temperature was treated with N-butylamine (0.115 mL, 1.17 mmol). The reaction mixture was stirred until a yellow solution resulted, then concentrated under reduced pressure after 1 h. Potassium carbonate (220 mg, 1.59 mmol) and DMF (4 mL) were added to the concentrate, and the reaction mixture was heated to 70° C. for 3 h, cooled to room temperature, and allowed to stand overnight. The next day the reaction mixture was poured into water, and the solid that formed was collected by filtration, washed with water, dissolved in methylene chloride and concentrated under reduced pressure to give title compound which was placed on high vac to remove residual solvent. MS (ESP): 400 (M+H+) for C16H18INO3; NMR: 0.90 (t, J=7 Hz, 3H), 1.28 (t, J=6 Hz, 3H), 1.33 (m, 2H), 1.71 (m, 2H), 4.22 (q, J=7 Hz, 2H), 4.35 (m, 2H), 7.64 (m, 1H), 8.05 (m, 1H), 8.50 (m, 1H), 8.70 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13]Br>C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCOc2ccc(C=O)cc2)cc1
Yield: 76 %

Procedure:
10.0 g of 4-hydroxybenzaldehyde and 8.3 g of 1,3-dibromopropane were reacted for 24 hours in 6.2 g of potassium carbonate solution in 100 ml of DMF under reflux. The reaction mixture was poured into cold distilled water to obtain a precipitate. After filtration and vacuum drying the precipitate, the resultant was recrystallized in ethanol to obtain the white product (XII-1). The product yield was 76%.
Reaction SMILES: [CH3:1][C:2]1([CH3:69])[O:7][CH2:6][C:5]([C:9]([O:11][CH2:12][C:13]([CH2:56][O:57][C:58]([C:60]2([CH3:68])[CH2:65][O:64][C:63]([CH3:67])([CH3:66])[O:62][CH2:61]2)=[O:59])([CH3:55])[C:14]([O:16][CH2:17][C:18]([CH2:23][O:24][C:25](=[O:54])[C:26]([CH2:41][O:42][C:43]([C:45]2([CH3:53])[CH2:50][O:49][C:48]([CH3:52])([CH3:51])[O:47][CH2:46]2)=[O:44])([CH2:28][O:29][C:30]([C:32]2([CH3:40])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]2)=[O:31])[CH3:27])([CH3:22])[C:19]([OH:21])=[O:20])=[O:15])=[O:10])([CH3:8])[CH2:4][O:3]1.[N+:70]([C:73]1[CH:74]=[C:75]([CH:91]=[C:92]([N+:94]([O-:96])=[O:95])[CH:93]=1)[C:76]([O:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89]Br)=[O:77])([O-:72])=[O:71]>>[CH3:66][C:63]1([CH3:67])[O:64][CH2:65][C:60]([C:58]([O:57][CH2:56][C:13]([CH2:12][O:11][C:9]([C:5]2([CH3:8])[CH2:6][O:7][C:2]([CH3:69])([CH3:1])[O:3][CH2:4]2)=[O:10])([CH3:55])[C:14]([O:16][CH2:17][C:18]([CH2:23][O:24][C:25](=[O:54])[C:26]([CH2:28][O:29][C:30]([C:32]2([CH3:40])[CH2:33][O:34][C:35]([CH3:38])([CH3:39])[O:36][CH2:37]2)=[O:31])([CH2:41][O:42][C:43]([C:45]2([CH3:53])[CH2:50][O:49][C:48]([CH3:51])([CH3:52])[O:47][CH2:46]2)=[O:44])[CH3:27])([CH3:22])[C:19]([O:21][CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][O:78][C:76](=[O:77])[C:75]2[CH:74]=[C:73]([N+:70]([O-:72])=[O:71])[CH:93]=[C:92]([N+:94]([O-:96])=[O:95])[CH:91]=2)=[O:20])=[O:15])=[O:59])([CH3:68])[CH2:61][O:62]1
Reactant: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC1(C)OCC(C)(C(=O)OCC(C)(COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCC(C)(COC(=O)C(C)(COC(=O)C2(C)COC(C)(C)OC2)COC(=O)C2(C)COC(C)(C)OC2)C(=O)O)CO1
Product: CC1(C)OCC(C)(C(=O)OCC(C)(COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCC(C)(COC(=O)C(C)(COC(=O)C2(C)COC(C)(C)OC2)COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCCCCCCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CO1

Procedure:
Preparation can be carried out analogously to Example 1 using 10.19 g (9.81 mmol) 2,2-bis[({2,2-bis[({(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl}oxy)methyl]propanoyl}oxy)methyl]propanoic acid, 1.494 g (9.81 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(l,5-5) (DBU) and 4.81 g (10.79 mmol) 11-bromoundecyl 3,5-dinitrobenzoate, to yield 11-[(3,5-dinitrobenzoyl)oxy]undecyl 2,2-bis[({2,2-bis[({(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl}oxy)methyl]propanoyl}oxy)methyl]propanoate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1>C1CCCCC1>[CH:10]1([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCCc1ccccc1
Reactant: C1=CCCCCCC1
Solvent: C1CCCCC1
Product: c1ccc(CCOC2CCCCCCC2)cc1
Temperature: 83 °C

Procedure:
A mixture of 183 g phenylethyl alcohol, 980 g cyclohexane and 14 g AMBERLYST® 15 was heated to reflux (83° C.) with stirring. cyclooctene over a period of 3 hrs. After refluxing for 13 hrs at 83-89° C. the mixture was filtrated and concentrated on a rotatory evaporator at 45° C. and 25 mbar resulting in 233 g concentrate, containing 17% cyclooctene, 58% phenylethyl alcohol and 18% phenylethyl cyclooctyl ether and 2% diphenylethyl ether by GC analysis, which was vacuum distilled. The fraction with a boiling range of 89-103° C. at 0.7 mbar (13 g containing 7% phenylethyl alcohol, 80% phenylethyl cyclooctyl ether and 10% diphenylethyl ether by GC analysis) was subjected to flash column chromatography over silica with a 1:25 diethyl ether/pentane mixture, yielding 5 g phenylethyl cyclooctyl ether of 97.4% purity by GC analysis, nD20=1.5175.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[OH:12].S(Cl)([Cl:16])(=O)=O.O>P(OC)(OC)(OC)=O>[Cl:16][C:6]1[C:5]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:4][C:3]([OH:12])=[C:2]([I:1])[CH:7]=1
Reactant: CC(C)(C)c1ccc(I)c(O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: COP(=O)(OC)OC
Solvent: O
Product: CC(C)(C)c1cc(O)c(I)cc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To 35 mL of trimethyl phosphate (TMP) at 0° C. to 10° C. add 2-iodo-5-(1,1-dimethylethyl)phenol (6.61 g, 23.95 mmol, Preparation 42). To this solution add dropwise over the period of one minute sulfuryl chloride (2.0 mL, 24.67 mmol) in 35 mL of TMP, and then stir the resulting mixture for 30 minutes still at 0-10° C. To the reaction mixture add 130 mL of water, and then extract the resulting quenchate into CH2Cl2. Dry combined organic phases over anhydrous MgSO4, filter through silica gel, and concentrate filtrate. Purify residue by flash chromatography using 5% ethyl acetate in hexanes to give 3.79 g (51%) of 4-chloro-2-iodo-5-(1,1-dimethylethyl)phenol as a golden oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.05 (s, 1H), 5.21 (s, 1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 153.73, 149.02, 139.63, 125.69, 114.23, 81.61, 77.32, 76.68, 36.03, 29.29. MS m/e 310.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:47][C:29]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CN(C)CCN(C)C>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:29]=[O:47])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CN(C)CCN(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 100 °C
Yield: 14.7 %

Procedure:
A reaction autoclave was charged with 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (0.10 g, 0.22 mmol), palladium dichloride cyclooctadiene complex (1.6 mg, 2.5 mol-%), xanthphos (9.7 mg, 7.5 mol-%), N,N,N′,N′-tetramethylethylene diamine (19.3 mg, 0.75 equiv.) and DMF (2 mL) and purged with synthesis gas (carbon monoxide:hydrogen=1:1) to 5 bar. The reaction autoclave was heated to 100° C. for 16 h and then cooled to ambient temperature. After release of the pressure, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel to yield the title compound (13 mg, 15%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a round-bottom flask containing diethyl 2-(4-benzyloxy-2-nitrophenyl) malonate (4c) (2.00 g, 5.17 mmol) was added EtOH (45 mL) and 10% NaOH (60 mL) producing a dark brown solution. The solution was refluxed for 3 h and checked by TLC (CHCl3), at which time the solution was slightly yellowish and clear. The EtOH was removed under reduced pressure to form a yellow suspension and sufficient THF (30 mL) was added to produce a clear yellow solution which was placed in an ice bath and stirred. 6M HCl (30 mL) was slowly added to the solution to reach pH 1. The light orange solution was refluxed for another hour, at which time two layers formed. The top THF layer was collected, and the aqueous solution was extracted with CHCl3 (100 mL). The organic layers were combined and dried with anhydrous sodium sulfate. The solution was then filtered, and the filtrate was concentrated to produce 4-benzyloxy-2-nitrophenylacetic acid as an orange solid. The solid was then placed on a high vacuum and dried (1.41 g, 4.91 mmol, 95%). Mp 145-152° C.; TLC (CHCl3) Rf=0.15; 1H-NMR (CDCl3, 300 MHz) 7.76 (d, 2.7, 1H), 7.41 (m, 5H), 7.26 (d, 8.7, 1H), 7.21 (dd, 2.7, 8.7, 1H), 5.13 (s, 2H), 4.00 (s, 2H); IR (CHCl3 cast) 3400-2600 (br), 3100, 1698, 1601, 1526, 1523, 1453, 1376, 1349, 1240, 1180, 1022, 848, 815, 760, 712; EI-MS m/z (relative intensity) 287 (M+, 10). Accurate mass (EI-MS) for C15H13NO5: calcd. 287.0794, obsd. 287.0799.
Reaction SMILES: [OH:1][C:2]1([C@H:6]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[C:17]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[N:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[OH:1][C:2]1([C@H:6]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[C:17]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[N:18][NH:19][C:13]=3[CH:12]=2)=[O:9])[CH2:3][CH2:4][CH2:5]1
Reactant: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](c3ccccc3)C3(O)CCC3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1n[nH]c2cc(NC(=O)N[C@@H](c3ccccc3)C3(O)CCC3)ncc12

Procedure:
In a manner similar to that described previously (e.g. Example 40, Step 3), (S)-1-((1-hydroxycyclobutyl)(phenyl)-methyl)-3-(3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea was treated with TFA and triethylsilane in DCM. The product (102) was purified by Reverse phase C-18 HPLC (eluting with Acetonitrile/Water+0.1% TFA). MS: [M+H]+ m/z 412. 1H NMR (500 MHz, DMSO) δ 12.24 (s, 1H), 9.48 (s, 1H), 8.61 (s, 1H), 7.85 (bs, 1H), 7.38 (t, 2H, J=7.5 Hz), 7.36 (s, 1H), 7.27 (t, 2H, J=7.5 Hz), 7.20 (t, 2H, J=7.5 Hz), 4.78 (d, 1H, J=9 Hz), 4.42 (t, 2H, J=4.5 Hz), 3.70 (t, 2H, J=4.5 Hz), 3.30 (s, 3H), 2.12 (1H, m), 2.00 (m, 2H), 1.79 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:10][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([CH3:40])[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C.O>[C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=3[C:15]([NH:39][S:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:40])(=[O:37])=[O:38])=[O:16])=[CH:10][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2cc(-c3ccccc3)nn2-c2ccccc2)c(C(=O)O)c1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Nc2cc(-c3ccccc3)nn2-c2ccccc2)c(C(=O)NS(=O)(=O)c2ccccc2C)c1
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of 2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid (Example 29) (100 mg, 0.26 mmol) in dichloromethane (3 mL) were added o-toluenesulfonamide (53.3 mg, 0.31 mmol), EDCI (99.47 mg, 0.52 mmol), DMAP (63.40 mg, 0.52 mmol), and triethylamine (0.127 mL, 0.91 mmol). The reaction mixture was stirred for 2 h, and then diluted with dichloromethane (10 mL) and water (20 mL). The organic phase was separated and then washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 90% EtOAc/hexane, to afford the product (13.9 mg, 10.0%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.74 (s, 3H) 6.67 (s, 1H), 7.03 (dd, 2H), 7.26-7.60 (m, 14H), 7.84 (dd, 2H), 7.94 (d, 1H). ES-MS m/z 539.1 (MH+); HPLC RT (min) 3.71.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].CCO.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34]Cl.C(N(C(C)C)CC)(C)C>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5](=[O:10])[CH2:6]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: COc1ccccc1OCC(O)CN1CCNCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1=O

Procedure:
To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 (0.7 g, 0.36 mmol) and diisopropylethyl amine (0.76 g, 0.36 mmol). The reaction mixture was heated at reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 14: Mass spectrum (M+1)=442.34
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9]O.O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH2:9][Cl:13])=[CH:4][N:5]=1
Reactant: OCc1cnc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cnc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a stirred solution of 41A (2.5 g, 14 mmol) in CH2Cl2 (20 mL) was added slowly SOCl2 (1.2 mL, 14 mmol) at room temperature. The reaction was stirred for 15 minutes, cooled to 0° C. and washed with saturated aqueous NaHCO3. The CH2Cl2 layer was dried (MgSO4), concentrated in vacuo and purified by flash chromatography (SiO2, CH2Cl2) to give 41B (1.3 g, 47%).