Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(OCCCO)cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (3.00 g) in N,N-dimethylformamide was treated with 3-bromo-1-propanol (1.60 ml) and potassium carbonate (2.82 g), and the mixture was heated at 60° C. for 8 hours. Then 3-bromo-1-propanol (1.60 ml) was added again, and the mixture was heated at 110° C. for 6 hours. After cooling, water and methylene chloride were added to the reaction mixture, and the organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with a mixed solvent of methylene chloride-methanol (from 0% to 6% gradient elution) to give 1-acetyl-4-[4-(3-hydroxypropyloxy)phenyl]piperazine (3.53 g) as a pale pink solid.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[S:10][CH:11]=[C:12]([Br:14])[CH:13]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16]>C1COCC1.[Cu]I>[Br:14][C:12]1[CH:13]=[C:9]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])[S:10][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1csc(Br)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 0.37 g (1.94 mmol) CuI, 2.24 g (1.94 mmol) tetrakis-triphenylphosphane-palladium and 16.2 mL triethylamine are added to a solution of 10.0 g (38.85 mmol) 2,4-dibromothiophene in 300 mL THF, the reaction mixture is cooled to −78° C. and then at this temperature a solution of 5.6 mL (38.85 mmol) ethynyl-trimethyl-silane in 250 mL THF is slowly added dropwise. After the addition has ended the mixture is allowed to heat up slowly to RT and stirred overnight. The mixture is evaporated down i.vac., the residue is combined with water, extracted exhaustively with DCM and the combined organic phases are dried over MgSO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, filtered to remove insoluble ingredients and the solvent is evaporated down. The residue is purified by chromatography (silica gel, PE).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].Cl>>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[C:26]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: OCCCO
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCCO)c1

Procedure:
To 1,3-propanediol (7 ml) is added sodium hydride (60% dispersion-type, 312 mg), and thereto is added 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (707 mg). The reaction mixture is reacted at 90° C. for two hours, and then reacted at 130° C. for one hour. The reaction solution is acidified with 10% hydrochloric acid, and extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and crystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{6-(3-hydroxypropyloxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (315 mg) as crystals.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:16]([O:18]CC2C=CC(OC)=CC=2)=[O:17])[CH2:4]1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1.Cl>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@H:15]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:46][CH2:47]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 111.9 %

Procedure:
The title compound was prepared from 33.5 mg (0.07 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid, 4-(methoxy)benzyl ester (from EXAMPLE 21, Step E) and 20.5 mg (0.07 mmol) of 4-(3-(4-fluorophenyl)propyl)-piperidine.HCl (from EXAMPLE 96, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 40 mg (80%) of the title compound: RF: 0.47 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.01-0.07 (m, 2H), 0.34-0.47 (m, 2H), 0.68 (m, 1H), 0.96-3.41 (m, 26H), 3.80 (s, 3H), 5.12 (ABq, J=11.9, 21), 6.82-7.34 (m, 12H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].B(F)(F)F.[OH-].[Na+].OO.C([O-])([O-])=[O:36].[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O.O(CC)CC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:36])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CCCC=CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Solvent: COCCOCCOC
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)N(CCCCO)CCCCCO
Reaction time: 1 h

Procedure:
Biphenyl-4-sulfonic acid-(4-hydroxybutyl)-penten-1-yl-amide (1 g) was dissolved in 0.5 M NaBH4 in diglyme (9 mL) and chilled in an ice bath. BF3. OEt2 (1 mL) in diglyme (4 mL) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 mL) was added. 3M NaOH (2 mL) was added followed by 30% H2O2 (3 mL). Anhydrous K2CO3 (5 g) was added and the solvent decanted. The K2CO3 was washed with ethyl acetate and the combined organics dried (Na2SO4) and evaporated. Distillation under vacuum removed most of the remaining diglyme. The residue was purified by column chromatography (ethyl acetate/petrol) to give the title compound as a white powder. δC (DMSO, 62.9 MHz): 22.7, 25.2, 28.3, 29.6, 32.1, 48.0, 60.3, 60.5, 127.1, 127.2, 127.6, 128.6, 129.2, 138.1, 138.4 and 144.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:32](=[O:33])[N:15]2[CH:16]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:35]1[NH:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[N:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[NH:39][C:35]=1[NH:12][CH:13]1[C:32](=[O:33])[N:15]2[CH:16]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])=[O:22])[C:17]([CH3:19])([CH3:20])[S:18][C@H:14]12
Reactant: CC(C)(C)C(=O)OCOC(=O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Reactant: Fc1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)C1N2C(=O)C(Nc3nc4ccccc4[nH]3)[C@H]2SC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of pivaloyloxymethyl 6-amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (200 mg.) and 2-fluorobenzimidazole (108 mg.) in methylene chloride (2 ml.) was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness and the residue was triturated with ether and hexane to give pivaloyloxymethyl 6-(benzimidazol-2-yl)amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (170 mg.) as a solid which had the following n.m.r. spectrum in d6DMSO: 1.14 (s, 9H); 1.43 (s, 3H); 1.60 (s, 3H); 2.24 (s, 3H); 4.55 (s, 1H); 5.5-5.9 (m, 4H); 7.0-7.54 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:27])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCc1nccs1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1nccs1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)[C:5]#[N:6].[BH4-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4C#N)cc23)ncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(CO)cc4C#N)cc23)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 3-chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]-5-formylbenzonitrile (24 mg, 0.06 mmol) in ethanol (IMS grade, 2.0 mL) and THF (2.0 mL) was added sodium borohydride (4 mg, 0.1 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was filtered and dried. This was then purified by silica gel flash chromatography (0-1% methanol in ethyl acetate) to afford the title compound as a white solid (4.0 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.46 (d, J=2.6 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.38 (s, 1H), 8.09 (m, 2H), 8.03 (d, J=3.5 Hz, 1H), 5.76 (t, J=5.8 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.46 (s, 3H). LCMS (Method B): RT=2.78 min, m/z: 410 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCCCC3)nc(N)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a 25 mL sealable tube under argon were combined 4-[2-amino-6-(1-piperidinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (0.106 g, 0.258 mmol), hydrazine monohydrate (0.51 mL, 10.3 mmol) and EtOH (5 mL). The vial was sealed and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated on a mixture of EtOH (1 mL) and water (9 mL). The mixture was filtered and the solid was washed with water and dried under vacuum at 40° C. to afford the title compound (66 mg, 80%) as a white solid. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 4H), 1.64 (m, 2H), 3.47-3.79 (m, 4H), 5.37 (s, 2H), 6.03 (s, 2H), 6.58 (s, 1H), 7.57 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.Cl>CS(C)=O>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([NH:7][N:8]2[CH:12]=[N:11][N:10]=[CH:9]2)=[CH:15][CH:16]=1
Reactant: Nn1cnnc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Nn2cnnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
3.36 Grams of potassium tert-butoxide was added to 15 ml of anhydrous dimethylsulfoxide and the mixture was stirred for 30 minutes at room temperature. Next, 2.52 g of 4-amino-4H-1,2,4-triazole was added to the solution. After the reaction mixture was stirred for 15 minutes at room temperature, 1.64 g of 4-fluorobenzotrifluoride was added thereto and the mixture was stirred for further 30 minutes at room temperature. Ice-water was added to the reaction mixture, which was then neutralized with a diluted hydrochloric acid. The crystals as precipitated out were collected by filtration to give 1.93 g of 4-[(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9]1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1
Reactant: O=C(N[C@H]1CCC[C@@H](Nc2cnccn2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCC[C@@H](Nc2cnccn2)C1
Reaction time: 3 h

Procedure:
To a solution of benzyl N-[(1S,3R)-3-(pyrazin-2-ylamino)cyclohexyl]carbamate, 74a, (0.040 g, 0.123 mmol) in methanol (10 mL) was added 10% Pd/C (0.043 g, 0.040 mmol) and the resulting suspension was stirred under an atmosphere of hydrogen for three hours until LCMS indicated completion of the reaction. The solution was filtered through a bed of celite and concentrated in vacuo to give a yellow solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:12])=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[H-].[Na+].C[N:16](C=O)C>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:12])=[CH:10][N:11]([NH2:16])[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]cc(C)c2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(n1)c(C)cn2N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine (17.3 mmol) in anhydrous DMF (20 mL) is added drop-wise to a stirred solution of NaH (60%, 260 mmol) in anhydrous DMF (35 mL) under N2 at 0° C. for 40 min and then stirred at 0° C. under nitrogen for 30 minutes. HOSA is added portion-wise for 45 minutes at 0° C. and then stirred at 0° C. for 2 hours. After quenching with ice-water (500 mL), the reaction mixture is extracted with ether (3×40 mL). The combined organic layer is washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 5-60% EtOAc in heptane to afford 5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.73 g) as a solid. MS: 178 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.34 (s, 3H), 4.04(s, 3H), 4.75(br, 2N—H), 6.63(d, H), 7.04(s, H), 7.60(d, H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [O-][n+]1ccc2cc(F)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(Cl)nccc2c1
Yield: 32.4 %

Procedure:
To a solution of 6-fluoroisoquinoline N-oxide (3 g, 18 mmol) in CHCl3 (50 mL) is added phosphorus oxychloride (5 mL, 54 mmol). The reaction mixture is refluxed for 2 h. The reaction mixture is poured into ice, and the pH is brought to pH 8-9 with 5 M NaOH. The aqueous phase is extracted with CH2Cl2 (3×). The combined organic layers are dried over MgSO4, and evaporated. Purification of the crude product by Biotage column eluted with 0-30% EtOAc/hexanes afforded 1.06 g (35%) of 1-chloro-6-fluoro-isoquinoline. LC/MS m/z=182 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12]Cl)=[N:6]2.[I-:14].[Na+].O.[Cl-].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12][I:14])=[N:6]2
Reactant: O=c1oc(CCl)nn2ccc(Cl)c12
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1oc(CI)nn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-chloro-2-(chloromethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one (2.87 g, 13.1 mmol) in 57 mL of dry acetone under inert atmosphere was added 3.93 g (26.2 mmol) of sodium iodide and this mixture was stirred at room temperature overnight. Next day, the reaction mixture was poured into a 1/1 mixture of water/brine (100 mL) and extracted with diethyl ether (2×75 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuum to afford 3.95 g of the title compound (95% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:58]1[CH2:62][CH2:61][CH:60]([CH2:63]O)[CH2:59]1)[CH3:57]>C1COCC1>[CH2:56]([CH:58]1[CH2:62][CH2:61][CH:60]([CH2:63][O:55][C:52]2[CH:51]=[CH:50][C:49]([C:46]3[N:47]=[CH:48][C:43]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:44][N:45]=3)=[CH:54][CH:53]=2)[CH2:59]1)[CH3:57]
Reactant: CCC1CCC(CO)C1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3CCC(CC)C3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 3-ethyl-cyclopentan-1-yl-methanol (prepared by LiAlH4 reduction of methyl 3-ethyl-cyclopentanecarboxylic acid). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(C=O)cn3)CC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(CO)cn3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
2-(4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl) piperidin-1-yl)pyrimidine-5-carbaldehyde (Step E product, 200 mg, 0.447 mmol) was dissolved in MeOH (20 ml) at RT and NaBH4 (66.2 mg, 0.670 mmol) was added. The mixture was stirred at RT for 30 min and TLC showed the SM was completely consumed. The mixture was diluted with EtOAc, washed with water, dried over MgSO4, evaporated to afford 198 mg of the product (99%) which was used for the next step. LC/MS (m/z): 450 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[NH:18][C:17]3[NH:16][C:15](=[O:19])[CH2:14][S:13][C:12]=3[C:11](=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:11]1[C:12]2[S:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=[C:9]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CSc2c([nH]c(SCc3ccccc3)nc2=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: O=C1CSc2c(Cl)nc(SCc3ccccc3)nc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of the product from step c) (1.5 g), phosphorus oxychloride (10 ml) and N,N-dimethyl aniline (1 ml) was heated under reflux for 2 hours. The mixture was allowed to cool to room temperature and poured carefully into a saturated sodium bicarbonate solution, and stirred for 15 mins. The crude product was extracted into ethyl acetate and purified (SiO2, dichloromethane as eluant) to give the subtitle compound (0.25 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:21](S(C3C=CC=CC=3)(=O)=O)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A solution of 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.6 g, 6.2 mmol) in ethanol (8 mL) and tetrahydrofuran (15 mL) was treated with an aqueous sodium hydroxide solution (10%, 20 mL). The reaction was stirred at 80° C. for 16 h. At this time, the reaction mixture was cooled to 25° C. and the resulting precipitate was collected by filtration. The solids were washed with petroleum ether and diethyl ether and then dried under vacuum to afford 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.2 g, 69%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 10.50 (s, 1H), 7.89 (dd, 1H, J1=4.8 Hz, J2=1.5 Hz), 7.84 (dd, 1H, J1=5.1 Hz, J2=1.5 Hz), 7.27-7.22 (m, 2H), 6.48 (d, 1H, J=2.1 Hz), 6.03 (d, 1H, J=10.5 Hz), 2.96-2.84 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 30 g of 2-anisic acid in 500 mL of round-bottom flask was added dropwise 50 mL of thionyl chloride. After all of the thionyl chloride was added the reaction mixture was stirred at room temperature for 18 hours. Excess thionyl chloride was then distilled off by water aspirator and the remaining liquid was vacuum distilled (82°/0.7 mm Hg). Desired 2-methoxybenzoyl chloride was obtained as a colorless liquid, 32 g.