Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C2C=CC(C(OC)=O)=CC=2)C=CC=C(C(OC)=O)[CH:2]=1.[C:21]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C(O)CCCO>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:31]12[C:21]3[CH:26]=[CH:25][C:24](=[CH:23][CH:22]=3)[C:27](=[O:28])[O:29][CH2:30][CH2:2][CH2:1][CH2:40][O:39][C:37](=[O:38])[C:34]([CH:35]=[CH:36]1)=[CH:33][CH:32]=2
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Reactant: COC(=O)c1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: OCCCCO
Product: O=C1OCCCCOC(=O)c2ccc(cc2)-c2ccc1cc2
Temperature: 281 °C
Reaction time: 0.13 h

Procedure:
Dimethyl 3,4'-biphenyldicarboxylate (5.41 g, 0.0200 mole), 21.62 g (0.0800 mole) of dimethyl 4,4'-biphenyldicarboxylate, 18.24 g (0.200 mole) of 1,4-butanediol and 20 μL of titanium tetraisopropoxide are added to a 100-mL round bottom flask equipped with a paddle stirrer, 15-cm heated Vigreux column, distillation head, condenser and graduated receiver. The apparatus is evacuated and refilled with nitrogen three times. A molten salt bath preheated to 220° C. is raised around the flask and after the monomers have melted, the stirrer is started. Methanol begins to distill and after 20 minutes, 7.0 mL is collected. During the next 27 minutes, the temperature is increased to 281° C. then the pressure is slowly reduced to 1 mm Hg. The excess 1,4-butanediol distills and viscosity of the reaction mass slowly increases. After an additional 8 minutes, the clear colorless polymer melt becomes very viscous and the polymerization is stopped. As it cools, the polymer melt quickly crystallizes to an opaque white solid which is then ground to a course powder. The polymer's inherent viscosity is 1.16 dL/g and its peak melting point is 266° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:30])[CH2:32][CH2:33][OH:34])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CNCCO
Product: CN(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 44 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylethanolamine to give the title compound in 44% yield; NMR Spectrum: 2.30 (s, 3H), 2.52-2.55 (m, 2H), 2.88 (t, 2H), 3.47-3.50 (m, 2H), 4.39 (t, 2H), 5.28 (s, 2H), 7.25 (d, 1H), 7.35-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 470 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH2:22])[CH3:21]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:22][CH2:20][CH3:21])=[O:13]
Reactant: CCN
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-1H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride (1.26 g, 10 mmol) and 1 drop of N,N-dimethylformamide. The mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was concentrated and the residue was dissolved in dichloromethane (20 mL). Ethylamine (1.1 g, 25 mmol) was added dropwise. The reaction was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated to provide the title compound (1.27 g). +ESI (M+H+1) 270.9.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH:7](Br)[C@H:6]1[F:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[C:24]([NH2:30])=[N:25][C:26](=[O:29])[NH:27][CH:28]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.C[Si](C)(C)N[Si](C)(C)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:27]2[CH:28]=[C:23]([Cl:22])[C:24]([NH2:30])=[N:25][C:26]2=[O:29])[C@H:6]1[F:21])(=[O:3])[CH3:2]
Reactant: Nc1nc(=O)[nH]cc1Cl
Reactant: CC(=O)O[C@H]1[C@H](F)C(Br)O[C@@H]1COC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(Cl)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (3.6 g, 0.01 mol) in methylene chloride (50 ml) is added a methylene chloride solution of 5-chloro-tris(trimethylsilyl)cystosine [prepared from 4.3 g, 0.03 mol. of 5-chlorocytosine as follows: a mixture of 5-chlorocytosine and 5-15 mg of ammonium sulfate in 43 ml of hexamethyldisilazane is heated to reflux until a clear solution is obtained. The excess hexamethyldisilazane is removed by evaporation in vacuo and the residue is dissolved in 25 ml of methylene chloride]. The mixture is stirred for 5 days at room temperature. Methanol (7 ml) is added to the reaction mixture, and the suspension is filtered through a Celite pad which is thoroughly washed with methylene chloride. The combined filtrate and washings are evaporated to dryness in vacuo and the residue is crystallized from ethanol to give 860 mg of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-chlorocytosine, m.p. 233°.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S(O[CH2:36][CH3:37])(=O)=O>C1COCC1>[CH2:36]([C@@H:15]([CH2:16][CH2:17][CH3:18])[C:14]([N:3]1[C@@H:2]([CH3:1])[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])=[O:19])[CH3:37]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a −78° C. stirred solution of the (4S,5R)-4-Methyl-3-pentanoyl-5-phenyl-oxazolidin-2-one (9.20 g, 35.2 mmol) in dry THF (150 mL) was added NaHMDS (42.2 mL, 1.0 M in THF) dropwise. After 1 hour, ethyl trifluoromethanesulfonate (5.93 mL, 45.7 mmol) was added dropwise and the reaction was stirred at −78° C. for an additional 2 hours. The reaction was warmed to −30° C. for 30 minutes and quenched with sat. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The organic extracts were combined and washed with brine (2×40 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 8.05 g of crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[F:12].[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[F:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]([OH:14])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(C=O)ccc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a solution of methyl-2-fluoro-5-formylbenzoate (2 g, 0.0109 mol) in dry DMF (75 mL) was added oxone (Aldrich, 6.75 g, 0.0109 mol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with 1.5M.HCl (50 mL) and the product was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over magnesium sulfate filtrated and concentrated to give 1.7 g (78%) of the titled compound as a solid. TLC: Chloroform/methanol (9/1), Rf=0.2, HPLC purity >99%. 1H NMR (DMSO) δ: 8.44 (m, 1H), 8.19 (m, 1H), 7.48 (m 1H), 3.88 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][N:20]([CH3:31])[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:32])[CH3:31])[S:22][C:23]=4[CH:29]=3)=[O:13])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(C2C=CCCC2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4C=CCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclohex-2-enyl-benzoic acid (0.079 g, 0.39 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.73 g, 0.30 mmol) to give the product (0.041 g, 31%). LC/MS: Retention time=5.09 min; (m/z): calcd for C25H30N40S (M+H)+: 435.6; found: 435.0.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH3:14])[CH:16]=2)[NH:20][C:19]1=[O:24]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 42.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 5-methyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 65 mg (42%) of the title compound as a brown solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[C:8]=2[F:43])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:42])[C:8]=2[F:43])=[O:44])[CH2:2][CH2:3]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1
Yield: 97.8 %

Procedure:
A solution of intermediate 24 (0.92 mmol) and TFA (10 mL) in DCM (50 mL) was stirred at RT for 3 h. The reaction mixture was concentrated, diluted with a minimum of MeOH and water was added. The pH was adjusted to ca pH12 with 4N NaOH. The fine suspension was sonicated for 15 min, collected by filtration, rinsed with water and dried under high vacuum to afford the title compound 25 (578 mg, 0.9 mmol, 98% yield, TFA salt) as a pale ivory solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.78-8.61 (m, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.02 (t, J=7.8 Hz, 1H), 7.90 (dd, J=8.1, 2.1 Hz, 1H), 7.28 (td, J=9.0, 2.1 Hz, 1H), 7.16-7.01 (m, 1H), 6.75 (d, J=5.3 Hz, 1H), 3.78 (d, J=6.1 Hz, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (q, J=6.0 Hz, 2H), 2.61-2.53 (m, 1H), 2.30-2.21 (m, 1H), 0.72-0.58 (m, 2H), 0.49-0.36 (m, 2H). MS (m/z): 526.6 (M+H).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].[NH3:14]>CO>[NH2:14][C:1]([CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: N
Reactant: CC(C)C(=O)CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)C(N)=CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Through a solution of 240 g of t-butyl isobutyrylacetate in 500 ml of methanol was passed 70 g of ammonia in 2 hours, maintaining the temperature at below 25° C. The resulting solution was sitrred at room temperature for 18 hours, after which the methanol was removed in vacuo. Methylene chloride was added and the suspension was filtered. The filtrate was concentrated on a rotary evaporator to give 180 g t-butyl 3-amino-4-methyl-2-pentenoate as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C[Si](OC(=O)C)(OC(=O)C)OC(=O)C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 91 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane, and 56 mg of toluene were placed in a glass reaction tube and 4 mg of methyltriacetoxysilane were added. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethylsiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 97.6% and n-octyltriethoxysilane was produced at a yield of 91%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1.[CH:12](=O)[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1>O.CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=2)=[N:8][CH:9]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: NNc1ccc(N)cn1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=NNc2ccc(N)cn2)cc1OC
Reaction time: 0.8 h

Procedure:
A solution of 5.0 g (0.025 mole) of the compound of Example I in a mixture of 13 ml of H2O and 20 ml of CH3OH was treated rapidly with a solution of 4.7 g (0.027 mole) of veratraldehyde in 40 ml of methanol using mechanical stirring. The reaction mixture was stirred rapidly for 0.8 hr and filtered. The yellow-brown solid was washed with 40 ml of methanol, ether and air dried, m.p. 232°-233°dec. yield: 7.2 g (83%). Recrystallization from methanol raised the melting point to 235°-236°, dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].[C:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)#[CH:26]>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][C:25]([C:27]5([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]5)=[CH:26][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml:0.3 ml) was degassed with N2 and Cl2Pd(PPh3)4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45° C. under N2, diluted to 20 ml with saturated NH4Cl and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.11 g, 78%), as pale paste. 1H-NMR (CDCl3) 8.34 (d, 1H, J=1.29 Hz); 8.24 (d, 1H, J=2.13 Hz); 8.08 (t, 1H, J=1.56 Hz); 8.05 (t, 1H, J=1.56 Hz); 7.53 (d, 1H, J=8.67 Hz); 7.03 (d, 1H, J=8.67 Hz); 6.75 (s, 1H); 4.26-4.19 (m, 4H); 4.06 (t, 2H, J=5.49 Hz); 1.94-1.87 (m, 2H); 1.41 (s, 9H); 1.36 (s, 6H); 1.1 (t, 3H, J=7.44 Hz).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10]C2C=C3C(=O)NC(=O)C3=CC=2)=[CH:3][CH:2]=1.O.[NH2:29]N>C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10][NH2:29])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2cc(CCC=Cc3ccc(-c4ccccc4)cc3)ccc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: NCCC=Cc1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 280 ml of ethanol, 7.9 g of the product of Stage A and 1.3 ml of hydrazine hydrate was refluxed and then allowed to return to ambient temperature. The precipitate was filtered off and washed with ethanol. After concentration, the product was poured into a 2N hydrochloric acid solution and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated under reduced pressure to obtain 2.89 g of the desired product melting at approximately 188°-194° C.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1)=[O:2].[CH3:41][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:4]1)[CH3:41]
Reactant: C[Mg]Br
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reaction time: 3 h

Procedure:
tert-Butyl (3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (360 mg) was dissolved in THF (4 ml), a solution (1M, 1.95 ml) of methyl magnesium bromide in THE was added under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (325 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:20]N(C)C(=O)C>>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.22 g) is added to a solution of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.49 g) in N,N-dimethylacetamide (5 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room temperature for 1.5 h. Then, the mixture is cooled in an ice bath and methyl iodide (0.63 mL) is added. The cooling bath is removed and the mixture is stirred at room temperature overnight. 1 M aqueous NaOH solution (6 mL) is added and the mixture is stirred at room temperature for another 12 h. Then diethyl ether is added and the aqueous phase is separated. The organic phase is extracted three times with water and the aqueous extracts and phase are combined and acidified using 2 M aqueous KHSO4 solution. The acidic aqueous phase is extracted with diethyl ether and the combined organic extracts are dried (Na2SO4). The solvent is evaporated to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:11])=[O:10].[OH-].[Na+:13]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O-:11])=[O:10].[Na+:13]
Reactant: Cc1ccc(Br)c(S(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)c(S(=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
49.6 g of 2-bromo-5-methylbenzenesulfinic acid are dissolved in 400 ml of methanol and treated with an equimolar amount of NaOH in 50 ml of water. The mixture is stirred at RT for 3 hours, the solution is filtered off and subsequently the solvents are removed in vacuo. Finally, water residues are removed azeotropically with 50 ml of toluene. The solid residue is dried over P4O10 in vacuo and 54.0 g of product are obtained, mp 288-290° C. (with decomposition).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:27]1[C:30]2([CH2:33][O:32][CH2:31]2)[CH2:29][CH2:28]1.C([O-])(=O)C([O-])=O>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([N:27]3[C:30]4([CH2:33][O:32][CH2:31]4)[CH2:29][CH2:28]3)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: C1CC2(COC2)N1
Agent: O=C([O-])C(=O)[O-]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)N1CCC12COC2

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and 6-Oxa-1-azaspiro[3.3]heptane, ethanedioate (1:2) (CAN 1380571-72-1) as starting materials and isolated (27 mg, 46%); MS (ESI, m/z): 456.6 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[C:13]#[N:14].O>C1COCC1>[C:13]([C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:15])=[O:2])#[N:14]
Reactant: COC(=O)Cc1ccc(OC)cc1C#N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)c(C#N)c1
Temperature: 55 °C
Yield: 76.9 %

Procedure:
The (2-cyano-4-methoxy-phenyl)-acetic acid methyl ester (120 mg, 0.585 mmol) was dissolved in 10 mL THF and 2 mL water and LiOH monohydrate (101 mg, 2.34 mmol) was added. The mixture was heated at 55° C. overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 30 mL water and adjusted to pH ˜14 with aqueous 1N NaOH. The aqueous layer was washed with 50 mL of ethyl acetate. The organic extract was discarded and the aqueous phase was treated with 1N HCl (aq.) to pH˜2-3. The aqueous solution was washed with 75 mL ethyl acetate and the organic solution was dried (MgSO4), filtered and concentrated to give 86 mg (77%) of the title compound (SM-1ah) as a yellow solid. MS (ES+) 192.2 (M+H)+ 1H NMR (CDCl3) δ 3.81 (s, 3H), 3.84 (s, 2H), 7.09 (dd, 1H), 7.13 (d, 1H), 7.30 (d, 1H), 10.22 (br s, 1H).