Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][N:14]([CH3:20])[CH2:13]3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C23CNCC2C3)c2ccccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C23CC2CN(C)C3)c2ccccc12

Procedure:
A stirred solution/suspension of 1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (85 mg, 0.38 mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde (0.23 mL, 3.0 mmol), then with sodium triacetoxyborohydride (318 mg, 1.5 mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride containing 2-propanol (2×10 mL). The combined organic solution was dried (MgSO4) and concentrated in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (76 mg, 84%, essentially pure without chromatography). This was dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with ether, collected, and dried in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane, hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 238.1. 1H NMR (CDCl3) δ □ 12.70 (br s, 1H), 8.16 (m, 1H), 8.04 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H), 4.20 (m, 1H), 4.06 (m, 1H), 3.50 (m, 1H), 3.14 (m, 1H), 2.90 (d, 3H, J=5 Hz), 2.68 (s, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 1.22 (m, 1H). 13C NMR (CDCl3) δ 135.73, 133.21, 131.70, 126.81, 126.35, 126.33, 125.41, 124.54, 61.65, 57.62, 41.52, 30.97, 22.37, 19.75.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37][O:38]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:38][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.72 (d, 1H, J=3.52 Hz), 7.45 (d, 1H, J=3.52 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.12-7.05 (m, 2H), 6.88 (d, 1H, J=7.82 Hz), 6.84-6.79 (m, 3H), 6.62 (d, 1H, J=6.65 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.08 (d, 1H, J=14.08 Hz), 3.00 (t, 2H, J=6.26 Hz), 2.37 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C27H28NO6S 494.1637, found 494.1640.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21]>CN(C=O)C.O.[Cl-].[Na+].O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccc(OC)nc2)C(C)C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (2 g, 9.79 mmol) in DMF (40 mL) at 0° C. was added NaH (60% in oil, 431 mg, 10.8 mmol). The reaction was stirred at 0° C. for 0.5 hour and a solution of 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 1 (B) (2.95 g, 10.28 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 2 hours and was diluted with water, brine, and CH2Cl2. The aqueous solution was washed with CH2Cl2 (3×) and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (hexanes to 70% EtOAc in hexanes) provided 2.87 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.14 (s) and 7.93 (s, total 1H), 7.54 (m, 1H), 7.31 (m, 1H), 7.24-7.08 (m, 3H), 6.80 (m, 1H), 5.05 (m, 1H), 4.29 (m, 2H), 4.09 (m, 1H), 3.95 (m, 3H), 3.67 (d, 1H), 3.31 (d, 1H), 3.08 (d, 1H), 1.32 (m, 3H), 1.09 (m, 6H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1F
Reactant: OCC1CCNCC1
Product: O=Cc1ccccc1N1CCC(CO)CC1

Procedure:
Prepared from 2-fluorobenzaldehyde and 4-hydroxymethylpiperidine.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C(N(CC)CC)C.Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCO)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
8.55 g (0.15 mol) of propargyl alcohol and 152 ml (110 g, 1.09 mol) of triethylamine are added to a solution of 20.2 g (0.1 mol) of 4-bromonitrobenzene in 285 ml of acetonitrile. The reaction solution is heated to 100° C. 11.9 g (10 mmol) of Pd(Pph3)4 and 3.94 g (20 mmol) of copper (I) iodide are added. After 10 minutes the solvent is eliminated in vacuo and the residue taken up in ethyl acetate. It is washed with water and ammonia water, filtered through Celite and the solvent is eliminated in vacuo. The product is obtained by chromatography on silica gel (dichloromethane/methanol=10:1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.44 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then 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 colorless solid (0.6 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Solvent: ClCCl
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 30 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-chlorobenzene boronic acid (216 mg, 1.38 mmol) and [Cu(OH)TMEDA]2Cl2 (113 mg, 0.24 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0->3:2 gradient) and by recrystallization from diisopropylether. The desired compound was obtained as a white solid (42 mg, 19%), MS: m/e 329.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.CC[O:23][CH2:24][CH3:25].[OH-].[Na+].[C:28]([OH:31])(=[O:30])[CH3:29]>B(F)(F)F.O>[C:24]([OH:23])(=[O:1])/[CH:25]=[CH:29]/[C:28]([OH:31])=[O:30].[CH3:7][N:4]1[CH2:5][CH:6]=[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1
Reactant: CCOCC
Reactant: CC(=O)O
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)C1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CC=C(c2ccccc2Cc2ccccc2)C1
Product: O=C(O)/C=C/C(=O)O
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A solution of 2.60 g of 3-hydroxy-1-methyl-3-(α-phenyl-2-tolyl)pyrrolidine of Example 53, in 30 ml of acetic acid and 2 ml of BF3.ether is stirred at 50°-60° C. for 21/2 hours and 16 hours at room temperature. The mixture is diluted with 30 ml of H2O, is made alkaline with NaOH, and extracted with CH2Cl2. The CH2Cl2 solution is dried (Na2SO4) and concentrated to an oil. A portion of the oil is dissolved in 10 ml of acetic acid and stirred with 0.7 ml of H2SO4 at 55° C. for 2 hours. A solution of the resultant oil in 15 ml of acetone is heated with 1.1 g of fumaric acid for dissolving and after cooling a product is isolated and recrystallized from acetone (60 ml) to provide 1-methyl-3-(α-phenyl-2-tolyl)-3 -pyrroline fumarate, mp 131°-132.5° C.
Reaction SMILES: [Na].[OH:2][C:3]1([CH3:12])[CH2:7][CH2:6][C:5](=[N:8]O)[C:4]1([CH3:11])[CH3:10]>C(O)CC.[Cl-].[Na+].O>[NH2:8][CH:5]1[CH2:6][CH2:7][C:3]([CH3:12])([OH:2])[C:4]1([CH3:11])[CH3:10]
Reactant: CC1(O)CCC(=NO)C1(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC1(O)CCC(N)C1(C)C
Temperature: 25 °C
Yield: 110.4 %

Procedure:
Sodium (4.63 g, 201 mmol) was added in small portions over 1 h to a solution of the crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g, from Step 2) in n-propanol (80 mL) at 80° C. The resultant mixture stirred at 80° C. for 2 h, cooled to room temperature, poured into brine (100 mL) and extracted with dichloromethane (3×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give crude 3-amino-1,2,2-trimethylcyclopentanol (9.1 g), which was taken to the next reaction without purification.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30](C)[CH3:31])#N.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.CCCCCC.ClCCl.CO>CO>[CH:33]1([NH:37][C:31]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:28]=[CH:29][N:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCC1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 74 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (72 mg, 0.16 mmol) with cyclobutylamine (16 μL, 0.19 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 74% yield (56 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]([CH2:11][CH2:12][CH3:13])[CH:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH3:22].[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCN1Nc2c(Cl)cccc2C1c1ccc(OC)cc1C
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(O)cc1C
Yield: 57.3 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(4-methoxy-2-methylphenyl)-2-propyl-2H-indazole (0.04 g, 0.13 mmol), boron tribromide (0.20 mL, 2.10 mmol) and 1.0 mL of cyclohexene to give the product (0.023 g) as a white solid.
Reaction SMILES: [C:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14](C)[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:19]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:20][CH2:21][C:22]#[CH:23].[C:30]1([S:36]([N:39]2[CH:43]=[C:42](I)[C:41]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)C>[CH:6]1([CH2:5][CH2:4][CH2:3][C:2]#[C:1][C:7]2[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)[CH2:25][CH2:24][CH2:19][CH2:20][CH2:21]1.[C:30]1([S:36]([N:39]2[CH:43]=[C:42]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:41]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)(=[O:37])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c(-c2cccnc2)n1
Reactant: C#CCCCC1CCCCC1
Reactant: CCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Solvent: CCOCC
Product: C(#Cc1c[nH]nc1-c1cccnc1)CCCC1CCCCC1
Product: O=S(=O)(c1ccccc1)n1cc(C#CCCCC2CCCCC2)c(-c2cccnc2)n1
Yield: 90 %

Procedure:
Compound 44E was prepared following the procedure as described for the synthesis of compound 44A (see Scheme 9) using pent-4-ynyl-cyclohexane and 3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flash chromatography with diethyl ether/PE 1/1) to afford 3-[1-phenylsulfonyl-4-(5-cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine (43E) as an oil (90%). 1H-NMR (400 MHz, CDCl3) δ 9.25 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 8.21 (s, 1H), 8.08-8.04 (m, 2H), 7.68 (bt, J=8 Hz, 1H), 7.57 (bt, J=8 Hz, 2H), 7.35-7.31 (m, 1H), 2.38 (t, J=7 Hz, 2H), 1.72-1.55 (m, 6H), 1.31-1.10 (m, 7H), 0.95-0.8 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH3:20][NH:21][CH:22](O)[CH3:23].C([OH:28])(C)C>ClCCl.O.O.O.O.[Fe](Cl)Cl>[CH3:20][N:21]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)[CH2:22][CH2:23][OH:28]
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: CC(C)O
Reactant: CNC(C)O
Agent: Cl[Fe]Cl
Solvent: O
Solvent: ClCCl
Product: CN(CCO)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reaction time: 14 h

Procedure:
A solution in 20 ml of dichloromethane of 1.61 g (6 mmol) of 4′-chloro-2,2′;6′,2″-terpyridine and 20 ml of N-methylaminoethanol are added in succession to a solution of 1.35 g (6.8 mmol) of iron(II) chloride tetrahydrate in 100 ml of isopropanol. The mixture is then boiled at reflux for 20 hours. The mixture is concentrated and a solution of 1.66 g of ammonium hexafluorophosphate in 10 ml of methanol is added. The resulting violet precipitate is washed four times using 50 ml of diethyl ether each time and once with 50 ml of water. The residue is then stirred for 14 hours in a solution of 4 g of sodium hydroxide in 300 ml of water/acetonitrile (1:1 v/v) in an oxygen atmosphere. Filtration is carried out over kieselguhr and the residue is washed with 50 ml of water, 50 ml of acetonitrile and 100 ml of dichloromethane. The filtrates are concentrated. Extraction is carried out four times with dichloromethane and the combined organic extracts are dried over sodium sulfate, filtered and concentrated. The residue is recrystallised from acetone/petroleum ether and acetonitrile; 2-(methyl-[2,2′;6′,2″]terpyridin-4′-yl-amino)-ethanol is obtained in the form of a white solid. MS (ESI pos., KF), m/z=345 (100, [M+K]+); 307 (35, [M+H]+).
Reaction SMILES: ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N.[Br:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([N+:26]([O-])=O)[C:20]=1[Cl:29]>>[Br:18][C:19]1[C:20]([Cl:29])=[C:21]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[NH2:26]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1Cl
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: Nc1cc(Cl)cc(Br)c1Cl
Yield: 24 %

Procedure:
This material was prepared according to the procedure used for SM-9, step 2 using 1-bromo-2,5-dichloro-3-nitrobenzene. Purification by flash chromatography (SiO2, 0-30% EtOAc in heptane) provided 3-bromo-2,5-dichloroaniline (24%): LCMS(m/z) 239.9 (MH+), tR=1.03 minutes; 1H NMR (400 MHz, CDCl3) δ 4.28 (br s, 2H) 6.71 (d, J=2.4 Hz, 1H) 7.02 (d, J=2.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:18]=[CH:17][C:16]=3[CH3:28])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].CCN(C(C)C)C(C)C.[C:42](O)(=[O:46])[C@@H:43]([CH3:45])[OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=3[CH3:28])[CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:42](=[O:46])[C@H:43]([OH:44])[CH3:45])[CH2:24][CH2:23]3)=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: Cc1ccc(CN2CCNCC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2CCN(C(=O)[C@@H](C)O)CC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(piperazin-1-ylmethyl)phenyl]-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (43-2) (2.3 g, 5.0 mmol, 1.0 eq) was dissolved in NMP (25 mL) and DIPEA (2.6 mL, 14.9 mmol, 3.0 eq), D-lactic acid (536 mg, 6.0 mmol, 1.2 eq) and HATU (2.8 g, 7.4 mmol, 1.5 eq) were added. The reaction mixture stirred at ambient temperature for 5 minutes and was then diluted with EtOAc (200 mL), washed with sodium bicarbonate (4×30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-40% IPA in DCM) to afford (2R)-1-[4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]-2-hydroxypropan-1-one (43-3) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.37 (d, J=8.4 Hz, 1 H); 7.35 (s, 1 H); 7.26 (s, 2 H); 7.08 (d, J=8.4 Hz, 1 H); 4.54 (q, J=6.8 Hz, 1 H); 3.98 (d, J=6.8 Hz, 2 H); 3.64 (m, 4 H); 3.57 (s, 2 H); 3.38 (s, 3 H); 2.49 (m, 4 H); 2.36 (s, 3 H); 2.21 (m, 1 H); 1.67 (m, 1 H); 1.43 (m, 1 H); 1.18 (d, J=6.8 Hz, 3 H). HRMS m/z (M+H) 536.2136 found, 536.2138 required.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH:14]=O)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccncc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 6-2 (2.20 g, 9.90 mmol, 1 equiv), diethyl malonate (3.00 mL, 19.8 mmol, 2.00 equiv), and piperidine (0.490 mL, 4.95 mmol, 0.500 equiv) in ethanol (50 mL) was heated at reflux for 20 h. The reaction mixture was allowed to cool to 23° C., then concentrated to about half its volume. The white crystals which formed were filtered and washed with cold ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,7]naphthyridine-3-carboxylic acid ethyl ester (6-3). 1H NMR (400 MHz, CDCl3) δ 12.15 (br s, 1H), 8.94 (s, 1H), 8.52 (d, 1H, J=5.2 Hz), 8.46 (s, 1H), 7.52 (d, 1H, J=5.2 Hz), 4.48 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz); TLC (EtOAc), Rf=0.13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([N+]#[C-])(C)([CH3:15])[CH3:14].N1[CH:23]=[CH:22][N:21]=C1.Cl.[OH-].[Na+].C>C(OCC)(=O)C>[CH2:23]([C:22]([NH2:21])=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1)[CH2:14][CH2:13][CH3:15]
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCC(N)=Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 2.3 gm of 4-(p-aminophenyl)-1-H-imidazole, 1.25 gm of t-butylisonitrile, 0.2 gm of AgCl, and 0.11 gm of imidazole was heated at 100° C. for 13 hours. The thick reaction mixture was treated with 10% HCl and ethyl acetate. The acid solution was adjusted to pH 6.5 with 10% NaOH, treated with charcoal, filtered, and adjusted to an alkaline pH. The layer which separated was extracted with ethyl acetate. After drying, the organic solution was evaporated to dryness to yield 0.38 gm of the desired compound.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C@@H:10]2[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]2[N:18]2[CH:25]=[C:24]([CH3:26])[C:22](=[O:23])[NH:21][C:19]2=[S:20])C(=O)C2=CC=CC=C12.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:25]=[C:24]([CH3:26])[C:22](=[O:23])[NH:21][C:19]1=[S:20]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN2C(=O)c3ccccc3C2=O)c(=S)[nH]c1=O
Agent: NN
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN)c(=S)[nH]c1=O
Temperature: 62.5 °C
Reaction time: 14 h

Procedure:
2′-O-Phthalimidopropyl-5-methyl-2-thiouridine (5.0 g, 15.8 mmol) is dissolved in 100 ml methanol in a 500 ml flask. Hydrazine (2.02 g, 63.2 mmol) is added and the mixture is heated to reflux (60-65° C.) with stirring for 14 hours. The solvent is evaporated in vacuo and the residue is dissolved in dichloromethane (150 ml) and extracted twice with an equal volume NH4OH. The organic layer is evaporated to yield the crude product. NMR is used to assay product purity. The product is used in subsequent reactions without further purification.