Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccccc1Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1

Procedure:
1-(3-Bromo-pyridin-2-yl)-3-(2-methoxy-phenyl)-thiourea was prepared from 3-bromo-pyridin-2-ylamine (5.0 g, 29.0 mmol) and 1-isothiocyanato-2-methoxy-benzene (4.0 mL, 29.0 mmol) in a manner analogous to Step 19a. The reaction product was isolated as a yellow solid (8.46 g, 86%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 13.62 (br s, 1H), 8.75-8.65 (m, 2H), 8.21 (dd, J=5.1, 1.5 Hz, 1H), 7.91 (dd, J=8.0, 1.6, Hz, 1H), 7.21 (dt, J=7.9, 1.5 Hz, 1H), 7.06-7.00 (m, 1H), 6.98-6.94 (m, 1H), 6.91 (dd, J=7.9, 5.0 Hz, 1H), 3.93 (s, 3H). MS=340 (MH)+. 20b) (8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine was prepared from 1-(3-bromo-pyridin-2-yl)-3-(2-methoxy-phenyl)-thiourea (2.0 g) in a manner analogous to Step 19b. The reaction product was isolated as a white solid (0.47 g, 25%). MP=186-187° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42 (d, J=6.7 Hz, 1H), 8.31 (dd, J=8.0, 1.1 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.06-7.01 (m, 1H), 6.95 (ddd, J=8.1, 8.1, 1.1 Hz, 1H), 6.91-6.88 (m, 1H), 6.78-6.73 (m, 1H), 3.90 (s, 3H). MS=319, 321 (MH)+. 20c) (2-Methoxy-phenyl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and (4-trifluoromethylphenyl)boronic acid (33.0 mg, 0.174 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2e. The reaction product was isolated as a white solid (0.032 g, 53%). MP=184-186° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (dd, J=6.8, 0.9 Hz, 1H), 8.38 (dd, J=8.0, 1.3 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 2H), 7.08-6.88 (m, 4H), 3.92 (s, 3H). MS=385 (MH)+.
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.F[C:35]1C=CC([N+]([O-])=O)=C(C)C=1>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[CH:11][C:10]=1[CH3:35])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Product: Cc1cc(N2CCN(C(=O)NCCCCC3CCSS3)CC2)ccc1N=C(N)c1cccs1
Yield: 16 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 5-fluoro-2-nitrotoluene replacing 2-fluoro-5-nitrotoluene. A white solid product is obtained (yield 16%). Melting point: 169.4-170.9° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][CH:15]=[N:14][N:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[CH:27][CH:26]=1)#[N:18].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:32](=[O:33])[C:31]([CH2:30][C:28]4[S:29][C:25]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[C:17]#[N:18])=[CH:26][CH:27]=4)=[C:37]([CH2:38][CH2:39][CH3:40])[N:13]4[N:14]=[CH:15][N:16]=[C:12]34)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)s1)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.10 g), ethyl 2-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-3-oxohexanoate (3.30 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight. The mixture was allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.85 g, 34%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)[CH:9]=1>C1COCC1.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH:9]=1
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
Lithium hydroxide (0.427 g, 17.8 mmol) was added to a stirred suspension of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.40 g, 8.92 mmol) in 20 mL of a 4:1 mixture of THF/ethanol. The mixture was stirred under nitrogen for 3 days at ambient temperature. The pH of the mixture was adjusted to neutral (by the addition of aqueous mineral acid) inducing a heavy precipitation of off-white colored solids. The solids were isolated by filtration and dried under reduced pressure to give the desired product (2.0 g; 93%).
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 85.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (85.9 mg, 0.14 mmol) prepared in Example 129a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (58.0 mg, 88%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[C:19]([OH:21])C)[CH:10](C(OC)=O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[CH:26]([NH2:28])=[NH:27]>CO>[CH2:1]([O:8][C:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:27][CH:26]=[N:28][C:19]=1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=CN
Reactant: COC(=O)C(C(=O)OC)C(OCc1ccccc1)=C(C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncnc(O)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
To a solution of dimethyl 2-benzyloxy-3-hydroxy-2-butenedicarboxylate (3.0 g) in methanol (60 ml) were added sodium methoxide (1.28 g) and formamidine hydrochloride (953 mg) under ice-cooling, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solvent was evaporated under reduced pressure, and water was added to dissolve the residue. 5% Aqueous potassium hydrogen sulfate solution was added, and the precipitated solid was collected by filtration, washed with water and dried to give methyl 5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (1.1 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=O)C.[OH-].[NH4+:13]>>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(N)n1
Agent: [OH-]
Product: NC(=O)c1csc(N)n1
Yield: 69 %

Procedure:
A solution of 2-amino-thiazole-4-carboxylic acid ethyl ester (258 mg, 1.5 mmol) (prepared as described in example 3, step 1) in concentrated aqueous ammonium hydroxide was heated to reflux for 8 hours. The reaction mixture was concentrated to dryness and residual water removed by azeotropic distillation with toluene. The residue was purified by chromatography over silica gel eluted with 2% v/v methanol in ethyl acetate to give 2-amino-thiazole-4-carboxylic acid amide as a colorless solid (149 mg, 69%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:67])([F:66])[F:65])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH2:58]>ClCCl>[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:66])([F:65])[F:67])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH:58][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CCOC1
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CCOC1
Reaction time: 24 h
Yield: 76.9 %

Procedure:
Tetrahydro-furan-3-carboxylic acid (81 mg), PyBOP (268 mg) and DIPEA (0.244 ml) are added to a solution of C-{2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methylamine (200 mg) in dichloromethane (4 ml). After 24 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield tetrahydro-furan-3-carboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (189 mg, compound 2.3 in Table 2) as a white foam. MS (HPLC/MS): 525 (MH+). Retention time: 1.97 min.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:34][CH:33]=1.Cl>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:45][CH2:46]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccsc2)C1
Yield: 74.6 %

Procedure:
The title compound was prepared from 21 mg (0.046 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-3-(cyclobutyl) propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 87, Step F), 11.7 mg (0.046 mmol) of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to provide 17.6 mg (72%) of the title compound: RF: 0.28 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 1.01-3.48 (m, 33H), 6.80-6.86 (m, 2H), 6.99-7.05 (m, 3H), 7.18 (m, 1H), 7.33 (m, 1H); ESI-MS 513 (M+H); HPLC A: 2.72min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>CC(C)=O.O>[C:1]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (18.5 ml) and an aqueous (50 ml) solution of sodium carbonate (17.0 g) were added dropwise to a solution of (S)-2-pyrrolidinemethanol (12.0 g) in a mixture of acetone (70 ml) and water (14 ml). After addition, the reaction mixture was stirred for 30 mins at room temperature. The reaction mixture was filtered. Water was added to the filtrate. The mixture was extracted with methylene chloride. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica-gel (hexane-EtOAc) to give the title compound (24.1 g) having the following physical data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:26][CH3:25])=[O:36])[CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (1.30 g) in dimethylformamide (20 ml) was added sodium hydride (oil, 216 mg), and the mixture was stirred at room temperature for 20 min. 3-Bromomethylbenzoic acid methyl ester (990 mg) was added and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→4/1) to give the title compound (719 mg, 39%).
Reaction SMILES: C1COCC1.[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([OH:19])=O)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][O:38][C:39]([C@@H:41]([NH2:51])[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:40].Cl>CN(C=O)C>[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([NH:51][C@H:41]([C:39]([O:38][CH3:37])=[O:40])[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 875.5 %

Procedure:
THF (700 ml) and BOC-Ser(Bzl)-OH (23.6 g, 0.8 M) and HOBT (108 g, 0.8 M) were added to H-Ser(Bzl)-Ome.HCl (196.57 g, 0.8 M); and DMF (200 ml) was added to prepare a solution. WSCI (146 ml, 0.8 M) was added dropwise thereto at 0° C. and the mixture was stirred at 0° C. for one hour and at room temperature overnight. The reaction mixture was concentrated in vacuo, and ethyl acetate (1 l.) was added to the residue, which was then washed with 5% sodium bicarbonate solution, 1 N HCl and water, each three times, in that order. Hexane was added to the oily product, which was then crystallized by adding crystalline seed. The material was then recrystallized from ether-hexane to obtain the substance [28] (340.4 g, yield: 87.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:11]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
5-Hydroxyindazole (3.00 g, 22.37 mmol), tert-butyldimethylsilyl chloride (4.05 g, 26.8 mmol) and imidazole (2.28 g, 33.5 mmol) were mixed in DCM (50 mL) and stirred at room temperature for 18 hours. The reaction mixture was poured into 0.5 N aqueous citric acid solution and extracted with DCM (3×25 mL). The combined organics were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0 to 50% EtOAc in hexane to yield the title compound as an orange solid (5.09 g, 90%):
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CS(=O)(=O)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CS(C)(=O)=O)c23)C1
Yield: 67.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl) acetamide (300 mg, 0.857 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (515 mg, 2.57 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(2-(methylsulfonyl)acetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (306 mg, 67.3% yield) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-].[Na+]>CO.Cl.O>[CH3:25][S:22]([N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:11]=[CH:10][CH:9]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(CN(Cc2cccc(CC(=O)O)c2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-{[methanesulfonyl-(4-methyl-benzyl)amino]-methyl}-phenyl)-acetic acid ethyl ester (101.4 mg, 0.27 mmol) in MeOH (3 mL) was added aqueous NaOH (2N, 0.4 mL). The reaction was stirred at room temperature for 1 h and was diluted with a 1:1 mixture of 1 N HCl and water. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (87 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCOCC4)c3)n2)n1
Yield: 75.6 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with morpholine (0.160 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.250 g, 75%) as a white solid. MS (ISP) 540.3 [(M+H)+]; mp 216° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]#[N:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1>C1COCC1>[Br:48][CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]#[N:13]
Reactant: Cc1cccc(COc2cccc(CO)c2)c1OCC#N
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(CBr)c2)c1OCC#N

Procedure:
To a solution of [2-(3-hydroxymethyl-phenoxymethyl)-6-methyl-phenoxy]-acetonitrile (230 mg, 0.81 mmol, example 75) in THF (3 mL) is added Ph3P (233 mg, 0.89 mmol) and stirred until homogeneous. Cooled solution to 0° C. then added portionwise NBS (151 mg, 0.85 mmol) and let stir 45 min. Concentrated reaction mixture under reduced pressure. The residue is purified by flash chromatography (silica, 40% CH2Cl2 in hexanes) to give the title compound as a white crystalline solid. MS (EI) 345, 347 (M)+, Br pattern.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C([N:17](CC)[C:18](=[O:24])[CH2:19]P(O)(O)=O)C.[H-].[Na+].O>C(COC)OC>[CH3:13]/[C:12](/[CH2:11][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:19]\[C:18]([NH2:17])=[O:24]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: CCN(CC)C(=O)CP(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C(N)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 5 g of E-geranylacetone in 90 ml of dimethoxyethane is treated at -20° with 25.1 g of phosphonoacetamide diethyl ester and 1.86 g of 50% sodium hydride dispersion in mineral oil. The reaction mixture is stirred at room temperature for 3.5 hours under argon. After the addition of water the mixture is extracted with ethyl acetate. The organic phase is dried and freed from solvent. Crystallization of the (2E/Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienamide (4:1 2E/Z mixture), which remains behind as the residue, from hexane gives white crystals, m.p. 51°-52.5°. This material is recrystallized a further twice from hexane, there being obtained pure (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienamide as a white crystalline material of m.p. 53°-53.5°.