Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.C(C1C=CC(N)=CC=1C(F)(F)F)#N.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[S:46])=[CH:40][C:39]=1[C:47]([F:50])([F:49])[F:48])#[N:37].[N-]=C=S>>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:46]2)=[CH:40][C:39]=1[C:47]([F:48])([F:49])[F:50])#[N:37]
Reactant: CCC(C)[C@H](N)CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [N-]=C=S
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)c(C(F)(F)F)c2)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-3-(trifluoromethyl)aniline was converted to 4-cyano-3-(trifluoromethyl)phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])=[O:33])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)c3ccccc3C(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of 2.97 g (0.01 mole) of 4'-amino-3,5-di-t-butyl-4-hydroxy biphenyl in 200 ml of diethyl ester was added a solution of 1.48 g (0.01 mole) of phthalic anhydride, and the resulting solution was stirred for about 16 hours. The solvents were removed under vacuum and the residual solid was recrystallized from a mixture of ethyl acetate and hexane to give 2.4 g of 2-{N-[4-(3,5-di-t-butyl-4-hydroxyphenyl)phenyl]carbamoyl} benzoic acid, m.p. 196°-198° C. Analysis: Calculated for C28H31NO4 ; % C, 75.5; % H, 7.0; % N, 3.1; Found: % C, 75.5; % H, 7.1; % N, 3.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][CH:10]1[C:15]([CH3:16])=[C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:13]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:12]2[S:11]1=[O:37]>ClCCl>[Br:9][CH:10]1[C:15]([CH2:16][Br:1])=[C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[N:13]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:12]2[S:11]1=[O:37]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
3.05 g of N-bromosuccinimide were added portionwise over 1.75 hours to an ice-cold solution of 4.6 g of t-butyl 2-bromo-3-methyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 350 ml of dichloromethane under the exposure to light of a tungsten lamp of 150 W. After the addition of N-bromosuccinimide was complete, the exposure was continued for one hour and the orange colored solution was evaporated to dryness under vacuo at low temperature. The residue was chromatographed over silica gel, using as initial eluent a 72:1 mixture of methylene chloride and acetone and then a 49:1 mixture of the same components to obtain 1.4 g of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide by evaporation to dryness of the suitable fractions.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.II.[Br:23]Br>C(Cl)Cl>[Br:23][CH:16]1[CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:19][NH:18][C:17]1=[O:20]
Reactant: O=C1CCCC(c2ccccc2)CN1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: O=C1NCC(c2ccccc2)CCC1Br
Reaction time: 0.33 h

Procedure:
4.4 g of phosphorus pentachloride were added slowly to 60 ml of methylene chloride containing 4.0 g of 6-phenylperhydroazepin-2-one [prepared as described in step (d) above], under a stream of nitrogen, keeping the temperature of the reaction solution at 0° to 5° C. After this addition, the reaction mixture was stirred for 20 minutes, and then 40 mg of iodine, followed by 21.1 ml of a 1M methylene chloride solution of bromine, were dropped into it at 0°-5° C. When this addition was complete, the reaction mixture was stirred for 1 hour. The volume of reaction mixture was reduced by half by evaporation under reduced pressure, to separate the title compound as crystals. After the addition of water, the separated crystals were collected by filtration and washed with ethyl acetate, to give 1.8 g of an isomer of the title compound, melting at 218°-219.5° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:37]5[CH2:38][CH2:39][CH2:40][CH:36]5[CH2:35][OH:34])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC[C@H]1CCCN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: OCC1CCCN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-2-(hydroxymethyl)pyrrolidine. A yellow solid 120 was obtained (0.027 g, 55%). 1H-NMR (CDCl3, 400 MHz) δ 2.06-2.11 (m, 2H), 2.16-21 (m, 2H), 3.46-3.53 (m, 1H), 3.63-3.76 (m, 3H), 4.28-4.34 (m, 4H), 4.61-4.66 (m, 1H), 6.78 (s, 1H), 6.92 (dd, J=1.4 Hz, 6.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.05 (dd, J=2.2 Hz, 8.0 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, 8.4 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@@H:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[O:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(O)C>[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][C@@H:10]([CH2:9][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21][C:20]#[N:23])[CH2:11]1
Reactant: C=CC#N
Reactant: c1ccc(CNC[C@H]2COc3cccnc3O2)cc1
Solvent: CCO
Product: N#CCCN(Cc1ccccc1)C[C@H]1COc2cccnc2O1
Yield: 99.5 %

Procedure:
Intermediate (55) (0.0195 mol) was dissolved in ethanol (50 ml). 2-Propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed overnight. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed for 2 hours. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed for 6 hours. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The product fractions were collected and the solvent was evaporated, yielding 6.0 g of (S)-3-[[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)methyl](phenylmethyl)amino]-propanenitrile (intermediate 56).
Reaction SMILES: C([N:4]1[CH:9]([CH2:10][C:11]#[N:12])[C:8](=[O:13])[NH:7][C:6](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21])(=O)C.O.NN>CN(C)C=O>[CH:14](=[C:6]1[NH:7][C:8](=[O:13])[CH:9]([CH2:10][C:11]#[N:12])[NH:4][C:5]1=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)N1C(=O)C(=Cc2ccccc2)NC(=O)C1CC#N
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1NC(=O)C(=Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 ml of dimethylformamide was added to the syrup of 1-acetyl-3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine and dissolved, followed by addition of 8.89 g (0.1776 mol) of hydrazine monohydrate. The solution was stirred at room temperature for 3 hours, concentrated, and the residue washed with water to obtain 4.91 g of 3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine. Yield (based on N,N'-diacetyl-3-cyanomethyl-2,5-dioxopiperazine): 45.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:17])=[C:7]3[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:15]1[CH2:14][CH2:13][CH2:12][C:8]2=[N:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6]([CH3:17])=[C:7]2[CH2:16]1)=[O:20])[CH3:23]
Reactant: Cc1ccc2c(C)c3c(nc2c1)CCCNC3
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCCc2nc3cc(C)ccc3c(C)c2C1
Yield: 42 %

Procedure:
8,11-Dimethyl-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 8,11-dimethyl-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 155.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 58.6 %

Procedure:
To a solution of ethyl 6-chloronicotinate (25.8 g, 0.139 mol) in ethanol was added sodiumborohydride (10.5 g, 0.278 mol), followed by stirring under an atmosphere of nitrogen gas at room temperature. After 41 hours, the reaction mixture was concentrated and then the residue was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=4:1, 2:1, and 3:2), to give the title compound (11.7 g, 58%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[CH:6]=1)C.[ClH:16]>>[ClH:16].[CH2:12]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([OH:15])=[O:3])[CH2:13][CH3:14]
Reactant: CCCc1cc(C(=O)OCC)cc(C)n1
Agent: Cl
Product: CCCc1cc(C(=O)O)cc(C)n1
Temperature: 25 °C

Procedure:
A solution of 2-propyl-6-methylisonicotinic acid ethyl ester (2.30 g, 11.0 mmol) in 6 N aq. HCl (40 mL) is stirred at 65° C. for 24 h before it is cooled to rt and extracted with diethyl ether (2×50 mL). The aq. phase is evaporated and the residue is dried under HV to give 2-propyl-6-methylisonicotinic acid hydrochloride (2.0 g) as a colourless solid, LC-MS: tR=0.44 min; [M+1]+=180.09; 1H NMR (D6-DMSO): δ 8.02 (s, 1H), 7.99 (s, 1H), 3.04 (t, J=7.5 Hz, 2H), 2.78 (s, 3H), 1.82-1.72 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=1.S(Cl)(Cl)=O.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C>CN(C)C=O.C(Cl)(Cl)Cl.ClCCl>[CH3:36][N:37]([CH3:38])[C:28]([C:26]1[O:27][C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])=[CH:24][CH:25]=1)=[O:30]
Reactant: CNC
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.1 %

Procedure:
A mixture of 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (4.85 g, 12 mmol), thionyl chloride (11.90 g, 100 mmol) and a few drops of N,N-dimethylformamide in chloroform (60 mL) was stirred at ambient temperature for 16 h. The solvent and excess of thionyl chloride were evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL). To the above solution (5 mL, 1.2 mmol) was added dimethylamine hydrochloride (0.81 g, 10 mmol), and triethylamine (1.01 g, 10 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and extracted with water (2×100 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography with dichloromethane-methanol (100:1-20:1) to afford N,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide (0.22 g, 42%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.31-6.90 (m, 5H), 6.43-6.37 (m, 3H), 4.97 (ABq, 2H), 4.78 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.11 (s, 6H), 2.96 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 161.6, 161.0, 159.4, 151.3, 147.5, 142.2, 132.6, 129.1, 124.1, 123.7, 121.0, 120.4, 119.5, 116.8, 110.4, 109.8, 92.9, 80.1, 72.6, 57.4, 37.1, 28.8; MS (ES+) m/z 431.1 (M+1).
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18]([CH:20](O)[CH3:21])=[CH:17][C:16]([F:23])=[CH:15][C:14]=3[N:13]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:12]=23)=[CH:6][CH:5]=1>[I-].[Zn+2].[I-]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18]([CH:20]([S:2][CH3:1])[CH3:21])=[CH:17][C:16]([F:23])=[CH:15][C:14]=3[N:13]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:12]=23)=[CH:6][CH:5]=1
Reactant: CS
Reactant: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Agent: [I-]
Agent: [Zn+2]
Product: CSC(C)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methanethiol was bubbled into a solution of [9-[(4-chlorophenyl)-sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo [1,2-a]indol-1-yl]acetic acid (Example 15A, Step 1, 48 mg, 0.1 mmol) in 5 mL of dichloro'methane at 0° C. and zinc iodide (5 mg, 0.015 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC with a C18 Zorbax column using a mixture of 5% iPrOH in hexanes+0.2% AcOH as eluant to provide the title compound as a white solid foam.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:3]=12.[C:19]([Zn]C#N)#[N:20].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CN(C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:8][C:6]1[CH:7]=[C:2]([C:19]#[N:20])[C:3]2[CH:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:5]=1
Reactant: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c2cnn(Cc3ccccc3)c2n1
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine (3.45 g, 11.42 mmol), dicyanozinc (1.542 g, 13.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.523 g, 0.571 mmol), SPhos (0.562 g, 1.370 mmol), DMF (49 mL), and water (0.5 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 120° C. for 2 hours, and then cooled to room temperature. The contents were concentrated to 50% volume and then 50 mL of 1N NaOH and 50 mL of EtOAc were added. The solids were filtered off. The phases were separated and the aqueous phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with water (3×50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product containing SPhos reagent (˜30-40%) was collected as 3.69 g and used without further purification. LCMS E-S (M+H)=249.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.77 (s, 3H), 5.73 (s, 2H), 7.08-7.44 (m, 6H), 8.16 (s, 1H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[O:16][CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[CH2:8][CH2:9][CH2:10][CH3:11]>CCOCC>[CH2:7]([O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCOc1cccc(OCCCC(=O)OCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCOc1cccc(OCCCCO)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 6.8 g of lithium aluminum hydride in 200 ml of anhydrous ether are added 26.2 g of ethyl 4-(3-pentyloxyphenoxy)butyrate dissolved in 100 ml of anhydrous ether. Addition is carried out at a rate which maintains reflux of the solvent. After 30 minutes, the mixture is cooled in an ice bath and quenched with water. 3N HCl is added; and the organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under vacuum to yield 4-[3-(pentyloxy)phenoxy]butanol.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([N:19]2[C:23](=[O:24])[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][NH:20]2)[CH:14]=1.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>C(O)C.O>[CH:1]1([CH2:7][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([N:19]3[C:23](=[O:24])[C:22]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][NH:20]3)[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=CC1CCCCC1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(CNCC2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.2 mg (100 μmol) of cyclohexanecarbaldehyde are initially charged, 34.0 mg (100 mol) of the compound from Example 4A, dissolved in 0.6 ml of ethanol, and 25.8 mg (200 μmol) of diisopropylethylamine are added and the mixture is stirred at RT overnight. 5.7 mg (150 μmol) of sodium borohydride are then added, and the mixture is shaken at RT for 3 h. 100 μl of water are then added, and the mixture is concentrated. The residue is taken up in DMSO, the precipitate is filtered off and the filtrate is purified by preparative HPLC (Method 4).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Triethylamine (2.91 g, 28.86 mmol) was added to the stirred solution of 4-methoxy-1-butanol (1.00 g, 9.62 mmol) in dichloromethane (15 mL) at 0° C. and stirred for 15 min. p-Toluene sulfonyl chloride (1.83 g, 9.62 mmol) was added and the mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched with ice-water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×5 mL) and the combined organic layers were washed with saturated sodium bicarbonate, water, and brine; dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (60-120 mesh) with 0% to 20% ethyl acetate in petroleum ether as eluent to afford 4-methoxybutyl-4-methylbenzenesulfonate (800 mg, 32%) as a liquid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:40]([F:43])([F:42])[F:41])=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[NH:33][CH:34]([CH2:37][CH2:38][CH3:39])[CH2:35][N:36]=4)=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:40]([F:43])([F:41])[F:42])=[C:16]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[NH:33][C:34]([CH2:37][CH2:38][CH3:39])=[CH:35][N:36]=4)=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH:17]=1
Reactant: CCCC1CN=C(c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cnc(-c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a stirred solution of oxalyl chloride (0.029 g, 0.228 mmol) in CH2Cl2 (1.5 mL) was added dropwise DMSO (0.028 g, 0.358 mmol) at −78° C. under nitrogen. The resulting mixture was stirred for 10 minutes. To this mixture was added dropwise a solution of (5-fluoro-2-trifluoromethylphenyl)-{4-[5-(5-propyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl]piperazin-1-yl}methanone (0.052 g, 0.112 mmol) in dichloromethane (1.5 mL). The resulting mixture was stirred for 10 minutes followed by the addition of triethylamine (0.056 g, 0.553 mmol). The reaction mixture was stirred at −78° C. for 1 h, and then allowed to warm to ambient temperature and quenched with water. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and then concentrated. The crude product was purified by preparative TLC to afford the title compound in 10% yield (0.005 g). 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.07 (dd, J=1.0, 9.0 Hz, 1H), 7.75 (dd, J=5.1, 8.8 Hz, 1H), 7.08 (dd, J=2.3, 7.9 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=9.0 Hz, 1H), 4.01-3.64 (m, 4H), 3.58-3.51 (m, 2H), 3.35-3.27 (m, 2H), 2.64-2.55 (m, 2H), 1.74-1.61 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (ES+) m/z 462 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:22])([CH3:21])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:21][C:2]([O:22][Si:31]([CH3:33])([CH3:32])[CH3:30])([CH3:1])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Cl
Reactant: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O[Si](C)(C)C
Temperature: 12.5 °C

Procedure:
2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5.0 gm) is dissolved in methylene chloride (25 ml) at 25-30° C., triethylamine (2.5 gm) is added and then the contents are cooled to 10-15° C. under N2 atmosphere. Trimethylsilyl chloride (2.5 gm) is slowly added to the reaction mass while maintaining the temperature between 10-15° C., the mass temperature is raised to 25-30° C. and maintained for 2 hours at the same temperature to give the reaction mass of 2,N-dimethyl-2-(trimethylsilyloxy)-N-(3,3-diphenylpropyl)-1-propanamine.