Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]([C:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)([CH2:7][CH2:8][CH3:9])[C:4]([O-:6])=[O:5])C.[OH-].[Na+]>CO.C(O)C>[O:16]=[C:15]1[N:14]([CH2:17][CH2:18][CH3:19])[C:13]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:12]=2[C:11]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[C:10]1[CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5]
Reactant: CCCn1c(=O)c(C(CC)(CCC)C(=O)[O-])c(-c2ccc(C)cc2)c2c3c(sc21)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccc(C)cc2)c2c3c(sc2n(CCC)c1=O)CCCC3
Temperature: 90 °C
Yield: 22.6 %

Procedure:
To a suspension of ethyl[2-oxo-1-propyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.071 g; 0.152 mmol) in a mixture of methanol and ethanol (2:1) (4.5 mL) was added a 5% sodium hydroxide solution (3.66 mL; 4.57 mmol) and the reaction mixture was heated to 90° C. for 7 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified to pH 2 with a 1N hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organics were combined, dried over sodium sulfate, concentrated under reduced pressure. Purification by preparative HPLC (method 2) furnished 0.015 g (22.7%) of 2-[2-oxo-1-propyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoic acid as a white solid. ESI/APCI(+): 438 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[C:14](OCCCC)(=O)[C:15]1C=CC(C([O-])=O)=C[CH:16]=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Reactant: CCCCOC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the procedure described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monobutyl terephthalate (10.0 g, 0.0384 mole), thionyl chloride (4.57, 0.0384 mole) and 40 ml of toluene. The yield of product was 8.5 g (92%). This material was used without further purification.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C@H:8]1[C:19]([OH:21])=O)=O)C.Cl.[CH3:24][C:25]([O:28][C:29]([C@@H:31]1[CH2:47][S:46][S:45][CH2:44][C@H:43]([NH2:48])[C:42](=[O:49])[NH:41][CH2:40][CH2:39][C:34]2([CH2:38][CH2:37][CH2:36][CH2:35]2)[C:33](=[O:50])[NH:32]1)=[O:30])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:27][C:25]([O:28][C:29]([C@@H:31]1[CH2:47][S:46][S:45][CH2:44][C@H:43]([NH:48][C:19]([C@@H:8]2[C@@H:9]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:10][CH2:11][NH:7]2)=[O:21])[C:42](=[O:49])[NH:41][CH2:40][CH2:39][C:34]2([CH2:35][CH2:36][CH2:37][CH2:38]2)[C:33](=[O:50])[NH:32]1)=[O:30])([CH3:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](N)C(=O)NCCC2(CCCC2)C(=O)N1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H]2NCC[C@@H]2c2ccc(O)cc2)C(=O)NCCC2(CCCC2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.4 %

Procedure:
To the mixture of (2S,3R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid (46 mg, 0.15 mmol) and (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester hydrochloride 70 mg, 0.15 mmol), prepared in Example 6, in 0.5 mL of DMF was added DIPEA (58 mg, 0.45 mmol) and HBTU (59 mg, 0.15 mmol). The solution was stirred at room temperature for 3 hours and was diluted with water to 3 mL. The resulting white precipitate was collected and was dried over night at reduced pressure to give 105 mg of (8R,13R)-13-[[[3(R)-(4-hydroxyphenyl)-2(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester as a white solid. This dried solid (85 mg) was the dissolved in 2 mL of dichloromethane and the solution was treated with 4 N HCl in dioxane (2 mL). The solution was stirred overnight and the solvent was then removed. The residue was purified by reversed-phase HPLC (5-95% of acetonitrile containing 0.75% of TFA in water oevr 40 min linear gradient) to give (8R,13R)-13-[[[3(R)-(4-hydroxyphenyl)-2(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid as a white solid (58 mg). HRMS (M+H): Obs. 551.2017, Calcd.551.1998.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H][H].N>C(O)C.[Ni]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1F
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccc(F)cc1F

Procedure:
13.9 g (0.10 mol) of 2,4-difluorobenzonitrile are dissolved in 100 ml of ethanol and hydrogenated in a pressurized reactor at 75°-80° C. using hydrogen gas after 1.4 g of Raney nickel in ethanol has been added and after 17 g (1.0 mol) of ammonia gas have been injected. The take-up of hydrogen is complete after about 2 hours. The reaction mixture is cooled, decompressed and filtered and then freed from solvent in a vacuum rotary evaporator. The resultant oil is subjected to fractional distillation at 70°-75° C. in vacuo (19 mbar). 9.5 g (66% of theory) of a colourless liquid are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:15]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)NCC(=O)O
Reaction time: 1.5 h

Procedure:
To a solution of L-valyl-glycine (1.0 g. 5.74 mmol) in 1 N NaOH (4.74 ml, 5.74 mmol) cooled to -5° C., 6.89 ml (689 mmol) of 1N NaOH and 968 1 (6.89 mmol) of benzoyl chloride were alternately stirred in for 30 minutes. After 90 minutes, the reaction mixture was diluted with water and washed with diethyl ether. The product was isolated by precipitation in the aqueous layer which was acidified to pH 1.5. The precipitate was then washed with diluted HCl, water, and ether. Recrystallization from water afforded 1.16 g (73% overall yield from 1): mp 190°-191° C.; Rf(D)=0.2.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[OH:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=O)[C@H:18]([OH:29])[CH2:17]4)[CH2:14][CH2:13][C:12]=2[CH:11]=1.[CH2:30]([NH2:32])[CH3:31].[BH4-].[Na+].C(=O)(O)[O-].[K+].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>CS(C)=O>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[CH2:30]([NH:32][C@H:19]1[C@H:18]([OH:29])[CH2:17][C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C:25]1[CH:26]=[CH:27][C:10]([OH:9])=[CH:11][C:12]=1[CH2:13][CH2:14]3)[CH3:31]
Reactant: CCN
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2=O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCN[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C

Procedure:
In a similar way as described in Example XXI 3,16α-dihydroxy-oestra-1,3,5(10)-trien-17-one diacetate was converted with ethylamine into the intermediate 17-ethylimine, which was reduced with sodium borohydride. Hydrolysis with potassium bicarbonate, followed by treatment with maleic acid gave the title compound, m.p. 147° C. (decomp.), [α]D +32.9° (c 1.07 in dimethylsulphoxide).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h

Procedure:
To a mixture of NaH (60% in oil, 60.9 g, 1.52 mol) in DMF (1500 mL) is carefully added crude (1,4-dioxa-spiro[4.5]dec-8-yl)methanol (15 g) in DMF (50 mL) at 10° C. under argon atmosphere and the mixture is stirred for 1 hour at the same temperature. To the mixture is added benzyl bromide (181 mL) 10° C., and stirring is continued for 3 hours at room temperature. After addition of H2O (70 mL) over 10 min, the mixture is poured into the mixture of H2O (4500 mL) and EtOAc (2000 mL). The water layer is extracted with EtOAc and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 8-benzyloxymethyl-1,4-dioxa-spiro[4.5]decane as a yellow oil. The crude product is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH3:19])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH3:19])[CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=1)[OH:8]
Reactant: CC(=O)Nc1ccc(C(=O)CN(C)Cc2ccc(Cl)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(O)CN(C)Cc2ccc(Cl)cc2Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(4-(2-((2,4-dichlorobenzyl)(methyl)amino)acetyl)phenyl)acetamide (1.5 g, 4.11 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the addition of NaBH4 (300 mg, 7.89 mmol, 2.06 equiv) in several batches at 0-5° C. The resulting solution was stirred for 2 h at 0-5° C. The reaction was then quenched by the addition of 5 mL of acetone. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 1.2 g (76%) of N-(4-(2-((2,4-dichlorobenzyl)(methyl)amino)-1-hydroxyethyl)phenyl)acetamide as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[C:13]([OH:16])#[C:14][CH3:15]>C(N(CC)CC)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.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:15][C:14]#[C:13][OH:16])=[CH:7][CH:6]=1
Reactant: CC#CO
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CC#CO)cc1
Temperature: 65 °C
Yield: 27.4 %

Procedure:
4-Bromophenylacetic acid methyl ester (23 g, 0.1 mol) was dissolved in dry triethylamine (80 ml) with propynol (5.82 ml, 0.1 mol). After the addition of cuprous iodide (0.3 g) and bis (triphenylphosphine)palladium (II) chloride (1 g) the reaction mixture was heated at 65° C. under nitrogen for 14 h. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate (500 ml) and washed successively with 0.5M citric acid solution (2×200 ml), saturated sodium hydrogen carbonate solution (2×200 ml) and brine (1×150 ml). The organic solution was dried (Na2SO4), filtered and concentrated in vacuo to give an oil which was purified by chromatography on silica gel using 20% ethyl acetate in hexane as eluent to give the required compound (5.6 g) as an oil. δ (360 MHz, CDCl3) 3.62 (2H, s, CH2CO2CH3), 3.69 (3H, s, CH2CO2CH3), 4.48 (1H, s, HOCH2), 7.22 (2H, d, J=8.2 Hz, ArH), 7.39 (2H, d, J=8.2 Hz, ArH); m/e 204 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH:17]([F:16])[F:29])=[C:21]([CH3:28])[CH:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ccc1OCC(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (580 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride (430 mg, 1.8 mmol, Amine-66) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:12])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) and potassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamide and treat with iodomethane (107 g, 753.9 mmol). Stir the reaction at room temperature for 3 hours. Filter off solids and pour into 6 L of water. Filter solids, wash several times with water, air dry and dissolve in ethyl acetate. Wash with water, followed by brine and then dry over sodium sulfate. Filter and concentrate under vacuum to 100 mL volume, at which point, solids start to crash out. Filter then concentrate down the filtrate to yield a second crop. Wash with hexane, combine all solids and vacuum dry to yield 112.3 g of off-white, solid: 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[C-:20]#[N:21].[Na+].O>CS(C)=O>[C:1]1([C:7]2([CH2:12][C:20]#[N:21])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccccc2)CCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (24-01) (6 g, 23.59 mmol) in dimethyl sulfoxide (18 mL) were added potassium iodide (392 mg, 2.59 mmol) and sodium cyanide (1.734 g, 35.384 mmol). The mixture was stirred for 140° C. for 16 h. After completion of the reaction, water was added and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, dried and evaporated to get a crude product which was purified using a normal silica column using 15% ethyl acetate in hexane to afford (1-phenyl-cyclopentyl)-acetonitrile (25-01) (2.25 g, 51.4%) as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: Nc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Under an inert atmosphere, 300 g of lithium aluminum hydride is provided in 3 1 of tetrahydrofran at 0° C. and treated in portions with 500 g of 5-amino-2-chlorobenzoic acid nindustrial, 85%). Thereafter the reaction mixture is heated slowly to room temperature and stirred over night at this temperature. For further processing the reaction mixture is cooled to 0° C. and the excessive lithium aluminum hydride is carefuly decomposed with saturated ammonium chloride solution. Thereafter the organic phase is separated from the deposit and this deposit is washed several times with acetic ester and methylene chloride. The united organic phases are washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. A yield of 242 g of crude 2-chloro-5-aminobenzyl alcohol is obtained the purity of which is adequate for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]2[N:56]=[CH:55][C:54]([NH2:57])=[CH:53][N:52]=2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:57][C:54]1[CH:53]=[N:52][C:51]([NH:50][C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=2)=[N:56][CH:55]=1)=[O:6]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Nc2ncc(N)cn2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(Nc2ncc(NC(=O)c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-(3-trifluoromethyl-benzoylamino)-benzoic acid (0.524 g, 1.53 mmol, 1.1 equiv) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.305 g, 1.74 mmol, 1.25 equiv) and diluted with DCM (10 mL). This was immediately treated with 4-methyl morpholine (0.458 mL, 4.16 mmol, 3 equiv) and allowed to stir at ambient temperature for 1 hour. Intermediate 68 (0.3 g, 1.38 mmol, 1 equiv) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were purified via silica gel chromatography. Eluting with 1:1 EtOAc in Hexanes afforded desired product. Beige solids (0.19 g, 26%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:10][CH:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:29])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[F:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:30]([OH:32])=[O:31])[NH2:8])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(Cc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N[C@@H](CC(Cc1ccc(CCCF)cc1)C(=O)O)C(=O)O

Procedure:
Di-tert-butyl N-(tert-butoxycarbonyl)-4-[4-(3-fluoropropyl)benzyl]glutamate (50 mg, 0.10 mmol) was dissolved in 3 ml trifluoroacetic acid and stirred at room temperature for 1d. Then, 5 ml toluene were added and the solution was concentrated in vacuo. The product was purified by preparative HPLC. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:23]([CH:24]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluorobenzonitrile.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([Cl:26])=[CH:11][N:10]=1.O>CS(C)=O>[Cl:26][C:12]1[C:13]2[C:18](=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:9]([NH:6][C:5]([NH2:7])=[NH:4])=[N:10][CH:11]=1
Reactant: Clc1cnc(Cl)c2cc(Sc3ccccc3)ccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N=C(N)Nc1ncc(Cl)c2ccc(Sc3ccccc3)cc12
Temperature: 80 °C
Yield: 66.7 %

Procedure:
NaH (13.6 mg, 80% dispersion by wt in mineral oil, 0.45 mmol) was added in one portion to a solution of guanidine hydrochloride (44 mg, 0.46 mmol) in DMSO (2 mL) and the mixture was heated at 80° C. under N2 for 10 min. 1,4-Dichloro-7-(phenylsulfanyl)isoquinoline (60 mg, 0.195 mmol) was added and the mixture heated at 80° C. for 1 h. The cooled mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was extracted with hexanes-i-Pr2O and this organic solution was decanted, and then stirred with a solution of HCl in Et2O to give a precipitate. The white solid was collected by filtration and dried in vacuo to give 4-chloro-1-guanidino-7-(phenylsulphanyl)isoquinoline (51 mg, 0.13 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2oc(Br)cc2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2oc(Br)cc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-6-bromo-2-(1-bromopropyl)furo[2,3-d]pyrimidin-4(3H)-one (1-4, 1 equiv) and N,N-dimethylethylenediamine (3 equiv) in ethanol is heated at reflux for 18 h. The reaction mixture is concentrated, and the residue is partitioned between EtOAc and brine. The organic layer is dried (MgSO4) and concentrated to provide 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-5)
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>ClCCl.CO>[N:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=2)[CH:19]=[C:18]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(aminocarbonyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 36) (167 mg, 0.47 mmol) in dichloromethane (14 ml) was added trifluoroacetic acid (7 ml). The resulting mixture was stirred at room temperature, under argon, for 2 hours and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D37). MS (ES+) m/e 257 [M+H]+.