Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)=[O:8].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14]([Cl:24])=[O:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of (12(b)) (495 mg; 1.5 mmole) in dichloromethane (25 mL) was cooled in an ice bath and DMF (1 drop) and oxalyl chloride (0.175 mL: 2.0 mmole) added dropwise. The solution was stirred at ambient temperature under argon for 4 hours. The dichloromethane and excess oxalyl chloride were removed in vacuo. The residue was azeotroped with toluene (2×15 mL) to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carbonyl-chloride (12(c)) which was used crude in the next step.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7]1)=[O:5])C>CO.C(OCC)(=O)C.[Pd]>[CH3:19][C:17]([CH3:20])([O:16][C:14]([N:11]1[CH2:10][CH2:9][C:8]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH2:13][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C(=O)O)c1ccccc12
Reaction time: 1 h
Yield: 916.7 %

Procedure:
To a suspension of Pd/C (300 mg) in methanol (20 ml) and ethyl acetate (10 ml) was added the title compound (1.2 g, 3.6 mmol) from Step B. The reaction mixture was purged with hydrogen and then stirred under a hydrogen balloon for 1 h. The mixture was filtered through celite and concentrated to give the title compound (1.1 g, 33 mmol). 1HNMR (200 MHz, CDCl3): 7.50-7.42 (m, 1 H), 7.34-7.12 (m, 3 H), 4.22-4.04 (m, 3 H), 3.06-2.84 (m, 2 H), 2.40 (d, 2 H), 1.88-1.6 (m, 4 H), 1.50 (s, 9 H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23](=[O:25])(=[O:24])[N:22](C(C)(C)C)[C:21](=[O:30])[CH:20]=2)=[CH:15][CH:14]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[N:31]([C@@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([O:37]C)=[O:36])=[C:32]=[O:33].C(N(CC)CC)C>CN(C)C=O>[CH2:7]([NH:6][C:4]([C@@H:3]([NH:2][C:32](=[O:33])[NH:31][C@@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([OH:37])=[O:36])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23](=[O:25])(=[O:24])[NH:22][C:21](=[O:30])[CH:20]=2)=[CH:15][CH:14]=1)=[O:5])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Reactant: CCCCCNC(=O)[C@@H](N)Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCNC(=O)[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A solution of 9-E (150 mg, 0.33 mmol), methyl (S)-(−)-2-isocyanato-3-phenylpropionate (120 μL, 0.66 mmol), and triethylamine (140 μL, 0.99 mmol) in dimethylformamide (2 mL) was stirred at 25° C. for 16 h. The reaction mixture was treated with Triamine-3 functionalized silica gel (1.2 mmol) and stirred for 1 h. The reaction mixture was filtered through a short plug of silica gel and washed with ethyl acetate (10 mL). The filtrate was concentrated and used without further purification. The crude product was dissolved in trifluoroacetic acid (10 mL) and heated at 70° C. for 16 h. The reaction mixture was concentrated and purified using preparative LCMS to yield the product (29 mg, 15%) as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.83 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 2H), 7.31–7.28 (m, 2H), 7.25–7.22 (m, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 2H), 7.02 (s, 1H), 4.53 (dd, J=7.8, 5.9 Hz, 1H), 4.44 (dd, J=7.3, 6.8 Hz, 1H), 3.69 (s, 3H), 3.19–3.04 (m, 4H), 3.00–2.94 (m, 2H), 1.42–1.35 (m, 2H), 1.34–1.28 (m, 2H), 1.24–1.19 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); LCMS found for C28H35N4O7S (M+H)+: m/z=571.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH2:57])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH:57][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.214 mL, 1.575 mmol) the title compound of Step C was obtained as a light yellow solid (653 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 1H), 7.52 (td, J=8.7, 6.0 Hz, 1H), 7.17-7.35 (m, 3H), 6.99 (d, J=5.3 Hz, 1H), 1.42 (s, 9H). MS (ESI): 556 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1C(C=O)COC1(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of racemate (SR)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After a TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>O1CCOCC1>[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCNCC1

Procedure:
A solution of Example 532B (2.1 g, 8.0 mmol) in 4HCl in dioxane (10 mL) at room temperature was stirred for 3 hours and concentrated to provide the desired product. MS (DCI) m/e 171 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(O)(C(=O)OCC)CCC3(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCC(C)(C)c2ccc(C(=O)Oc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/-) ethyl 4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate (Compound E54, 35.0 mg, 0.077 mmol) in 10 mL benzene was added a catalytic amount (approximately 2 mg) of p-toluenesulfonic acid monohydrate. The solution was heated to reflux under a Dean-Stark trap for 3 h, and then cooled to room temperature and stirred overnight. The solvent was removed under reduced pressure and the title compound isolated from the residue by column chromatography (10% EtOAc-hexanes).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=10.05 min. MS (ESI−): mass calcd. for C22H15Br2ClN4O5S2, 674.77; m/z found, 673/675 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.77 (s, 1H), 8.46-8.42 (m, 1H), 8.34-8.29 (m, 1H), 8.19-8.13 (m, 1H), 7.93-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.73-7.69 (m, 1H), 7.54-7.46 (m, 2H), 7.40-7.35 (m, 1H), 7.17-7.12 (m, 1H), 4.97-4.88 (m, 1H), 3.40-3.32 (m, 1H), 3.22-3.14 (m, 1H).
Reaction SMILES: [NH3:1].O1CCOCC1.[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[S:26][C:27]([S:30]([OH:33])(=O)=[O:31])=[CH:28][N:29]=2)[CH2:21][CH2:20]1)=[O:17]>>[NH2:1][S:30]([C:27]1[S:26][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]([C:10]3[NH:11][C:12]([CH3:15])=[C:13]([Cl:14])[C:9]=3[Cl:8])=[O:17])[CH2:20][CH2:21]2)=[N:29][CH:28]=1)(=[O:33])=[O:31]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(=O)(=O)O)s3)CC2)c(Cl)c1Cl
Reactant: N
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(N)(=O)=O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
0.5 M ammonia/dioxane (10 ml, 5 mmol) was added to 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-sulfonic acid (Example 254; 100 mg, 0.226 mmol) in a pressure bottle. The mixture was stirred at room temperature for 4 h. Excess solvent was removed in vacuo and the brown solid was dried in vacuo to give the title compound (56 mg).
Reaction SMILES: [ClH:1].[C:2](=[NH:10])(OC)[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[NH3:11]>>[ClH:1].[C:2](=[NH:10])([NH2:11])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCC(=N)OC
Reactant: N
Agent: Cl
Product: C=CCCCC(=N)N

Procedure:
Methyl 5-hexenimidoate hydrochloride (P3, 1.5 g) was dissolved in NH3 (2M in MeOH, 46 mL) and the mixture was heated to reflux for 2 h. Volatiles were evaporated in vacuo to give 1.45 g of the title compound as brown solid, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1](=[O:46])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:2][C@H:3]1[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5][C@@H:4]1[CH2:29][O:30][Si](C(C)(C)C)(C)C.CCOC(C)=O.Cl>CCO>[C:1](=[O:46])([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[O:2][C@H:3]1[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5][C@@H:4]1[CH2:29][OH:30]
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](CO)O4)c(=O)nc3o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL flask was added 20 mg (0.2 mmol) of (2R,3S,5R)-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3(2H)-yl)-2-((tert-butyldimethylsilyloxy)methyl)-tetrahydrofuran-3-yl benzyl carbonate, 2 mL of EtOAc, 2 mL of EtOH and 0.5 mL of 37% aqueous HCl. The mixture was stirred at rt for 0.5 h.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9]([Si:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10]>>[Si:11]([CH2:9][CH2:10][P:1]([O:5][CH2:6][CH3:7])([O:2][CH2:3][CH3:4])=[O:8])([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP([O-])OCC
Reactant: C=C[Si](OCC)(OCC)OCC
Product: CCO[Si](CCP(=O)(OCC)OCC)(OCC)OCC
Yield: 33 %

Procedure:
Compounds of Formula II can be synthesised via a free radical promoted addition of a dialkyl phosphite to vinyl trialkoxy silane and then distillation, according to the procedure of G. H. Barnes and M. P. David in J. Org. Chem., 25, 1191, (1960). In this paper Barnes and David reported the synthesis of a number of organosilicon phosphonate esters and acids. They utilised known procedures for the free radical addition of dialkyl phosphites to double bonds. The state of this art is described in Org. Reactions. Vol. 13, 218–222. They reacted diethyl phosphite with vinyl triethoxy silane at 120–130° C. in the presence of a free radical initiator. The desired product, (EtO)3SiCH2CH2PO(OEt)2, was obtained after careful distillation in 33% yield.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2.CI.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH3:24])[C:4]2[C:13](=[O:21])[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(=O)oc3ccccc3c2c1=O
Temperature: 80 °C

Procedure:
A mixture of ethyl 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]-pyridine-2-carboxylate (11.0 g, 0.0386 mole), methyl iodide (22.0 g, 0.154 mole) and potassium carbonate (10.7 g, 0.077 mole) in dimethylformamide (175 ml) is heated at 80° C. for 3 hours under nitrogen. The reaction mixture is cooled and poured into excess cold water. The product, which precipitated, is filtered off and recrystallized from dimethylformamide as white crystals (7.2 g, 62%), m.p. 203°-208° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:18]=2[N:19]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][C:15]1[N:16]([C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41])[C:17]2[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][C:18]=2[N:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2nc(SCc3ccccc3C(=O)OC(C)(C)C)[nH]c2cc1C
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc(SCc3ccccc3C(=O)OC(C)(C)C)n(C(=O)c3ccccc3)c2cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid t-butyl ester (30 mg, 0.082 mmol) was dissolved in 3 ml of chloroform, to which triethylamine (17 μl, 0.123 mmol) and benzoyl chloride (14 μl, 0.123 mmol) were sequentially added and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and 2-((5,6-dimethyl-1-(phenylcarbonyl)benzimidazole-2-ylthio)methyl)benzoic acid t-butyl ester was obtained (38 mg, yield quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(N)=O.Cl>[OH-].[Na+]>[CH3:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: N=CN
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: NC=O
Product: Cc1cccc2c(=O)[nH]cnc12
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
2-Amino-3-methylbenzoic acid (100 g, 0.66 mol), formamidine acetate (206 g, 1.98 mol) and formamide (26 mL, 0.6600 mol) were mixed in a 2 L R.B fitted with Mechanical stirrer. The reaction mixture was heated at 160° C. for 16 h. The reaction completion was monitored by LCMS. After completion, the reaction mixture was cooled to was RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reaction mixture neutralised with 1.5N HCl solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield (90 g, 86% yield) of the titled compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.21 (bs, 1H), 8.10 (s, 1H), 7.95-7.93 (dd, J=8.8, 7.9 Hz, 1H), 7.65-7.63 (d, J=7.9 Hz, 1H), 7.39-7.35 (t, J=15.2 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12]/[CH:13]=[CH:14]/[B:15]([OH:17])[OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:19]([C:22](O)([CH3:24])[CH3:23])([CH3:21])[CH3:20].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:20][C:19]1([CH3:21])[C:22]([CH3:24])([CH3:23])[O:16][B:15](/[CH:14]=[CH:13]/[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:17]1
Reactant: O=C(NC/C=C/B(O)O)OCc1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OB(/C=C/CNC(=O)OCc2ccccc2)OC1(C)C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A mixture of (E)-(3-(((benzyloxy)carbonyl)amino)prop-1-en-1-yl)boronic acid (2.38 g, 10.14 mmol), pinacol (1.418 g, 12 mmol), and magnesium sulfate (2 g, 16.62 mmol) in ether (25 mL) was stirred for 2 days. The mixture was filtered and concentrated. The crude material was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give (E)-benzyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate as a clear oil (1.6 g, 50%). LCMS: Rt=3.66 min, 77%, (M+H)+=318, (M−H)−=316.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:10]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc(F)c(B(O)O)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=Cc1ccc(F)c(-c2ccccn2)c1
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromopyridine (250 mg; 1.58 mmol), 2-fluoro-5-formylphenylboronic acid (265 mg; 1.58 mmol), and Pd(PPh3)4 (91 mg; 0.08 mmol) in toluene (1 ml), EtOH (1 ml), and aq. 2 M Na2CO3 (1.5 ml) was heated to 80° C., under nitrogen, for 17 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 4-fluoro-3-(pyridin-2-yl)benzaldehyde as a slightly yellow oil. LC-MS (conditions A): tR=0.51 min.; [M+H]+: 202.05 g/mol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:41]2([CH3:42])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:35]I)[CH2:21][CH2:22][C:23]([F:34])([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:9]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:41]2([CH3:42])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:35])[CH2:21][CH2:22][C:23]([F:33])([F:34])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:9]1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
By an alternative procedure, a mixture of 0.205 g (0.00025 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluoro-21-iodocholest-5-ene, 0.987 g (0.00030 mol) of tri-n-butyltin hydride and 3 mL of tetrahydrofuran were stirred at 25° C. for 18 hr under an argon atmosphere. The mixture was evaporated to dryness and the residue was purified by chromatography on 0.06-0.20 mm silica gel to yield [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, [α]D18 +2° (c 1, CHCl3).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)#[N:25]>C1C=CC=CC=1>[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(CCl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: N#Cc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Yield: 6.7 %

Procedure:
To a mixture of 1.2 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 50 ml of benzene was added 688 mg of 4-cyanobenzyl chloride and the mixture was stirred under reflux for 3 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 105 mg of 5-[4-(4-cyanobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[C:16]1([C:15]#[C:14][C:12]2[CH:13]=[C:8]([NH2:7])[CH:9]=[N:10][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cncc(C#Cc2ccccc2)c1
Yield: 80.6 %

Procedure:
Prepare essentially as described in EXAMPLE 2 from 5-phenylethynyl-pyridin-3-yl)-carbamic acid tert-butyl ester, (prepared as described in EXAMPLE 154), (0.380 g, 1.3 mmol) in 1,4-dioxane (1 mL) and hydrogen chloride (3 mL, 12 mmol) to give the title compound (280 mg, 81%).