Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]=[C:6]([S:9][CH3:10])[S:7][CH3:8].CC([O-])(C)C.[K+].[CH2:18]([N:20]=C=S)[CH3:19]>C1COCC1>[CH3:10][S:9][C:6]1[S:7][C:8]([NH:20][CH2:18][CH3:19])=[C:4]([C:3]([O:2][CH3:1])=[O:11])[N:5]=1
Reactant: CCN=C=S
Reactant: COC(=O)CN=C(SC)SC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1sc(SC)nc1C(=O)OC
Reaction time: 0.5 h

Procedure:
A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. calcd. for C8H13N2O5PS2+0.1HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[BrH:8]>CC(O)=O>[BrH:8].[NH2:1][C@@H:2]([CH2:6][CH2:5][Br:8])[C:3]([OH:4])=[O:7]
Reactant: N[C@H]1CCOC1=O
Agent: Br
Solvent: CC(=O)O
Product: N[C@@H](CCBr)C(=O)O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
(S)-3-aminodihydrofuran-2(3H)-one hudrochloride (10.30 g, 74.87 mmol) in 58 mL of 30% w/w HBr in HOAc was stirred at 65° C. for 30 hrs. The solvent was removed under reduced pressure and the resulted solid was suspended in MTBE (200 mL) and stirred for 30 min. The solid was collected by filtration and washed with MTBE (200 mL) and dried to give (S)-2-amino-4-bromobutanoic acid hydrobromide as white solid (19.33 g, 98%). 1H NMR (400 MHz, d6-DMSO) δ 8.37 (s, 3H), 4.01 (m, 1H), 3.65 (m, 2H), 2.33 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: CN
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: CNC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 78 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (81 mg, 78%), which was obtained as a white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12]I.[H-].[Na+]>O1CCCC1>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: OCCCc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a stirred solution of 3-(4-chlorophenyl)propanol (9.61 g, 54.17 mmol) and methyl iodide (7.0 ml, 112 mmol) in dry tetrahydrofuran (85 ml) under nitrogen was added 60% sodium hydride (2.83 g, 70.8 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was treated with ice/water (150 ml), extracted with methylene chloride (3×250 ml), and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Chromatography of the residual yellow oil on silica gel eluting with hexane afforded the title compound as a yellow oil (8.69 g, 86% from 3-(4-chlorophenyl)propionic acid) which was characterized by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH2:32])[CH3:31]>ClCCl.C(N(CC)C(C)C)(C)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH:32][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1)[CH3:31]
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: C[C@H](N)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1F
Yield: 97 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:21]=[C:22]([NH:26][C:5](=[O:7])[CH3:6])[CH:23]=[CH:24][CH:25]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)n(Cc2cccc(N)c2)c1=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(Cn2c(N)cc(=O)n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (3-nitrobenzyl)-urea [J. Med. Chem. 1996, 39, 1924 ] is converted into 6-amino-3-methyl-1-(3-nitro-benzyl)-1H-pyrimidine-2,4-dione, [M−H]− 275. A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd/C (0.484 g) in ethanol (200 ml) is hydrogenated at 1 atmosphere for 1.5 hours. The reaction mixture is filtered through a celite plug and evaporated to give 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt [M−H]− 245. Acetic anhydride (1.85 ml, 19.57 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (5.01 g, 16.35 mmol) in pyridine (50 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[3-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, 1H NMR (400 MHz, DMSO): δ: 2.00 (s 3H), 3.09 (s 3H), 4.72 (s 1H), 5.02 (s 2H), 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55 (d J 6 1H). Using the general procedure for Intermediate 1, this compound is converted into N-[3-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide [MH]+ 304.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:63]([CH2:65][C:66](O)=[O:67])#[N:64]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:66](=[O:67])[CH2:65][C:63]#[N:64])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,3-difluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (30 mL), HATU (400 mg, 1.05 mmol, 1.5 equiv), triethylamine (220 mg, 2.17 mmol, 3.0 equiv), and 2-cyanoacetic acid (90 mg, 1.06 mmol, 1.5 equiv). The resulting solution was stirred for 10 h at 25° C. and then washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 240 mg (69%) of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[C:27]2[CH:28]=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][C:26]=2[N:25]=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[C:4]([N:8]4[C:16]5[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=5[C:10]5[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]4=5)[CH:5]=[CH:6][CH:7]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc4[nH]cnc4c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-benzimidazole-5-boronic acid pinacol ester (137 mg, 0.561 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(1H-benzo[d]imidazol-5-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 9.08 (s, 1H), 8.02 (s, 1H), 7.86 (m, 3H), 7.72 (m, 2H), 7.48 (d, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.02-3.2 (m, 5H), 2.41 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26])#[N:21].CCN=C=NCCCN(C)C>ClCCl>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH2:2][CH3:3])=[N:5][N:6]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=[O:26])#[N:21]
Reactant: CCc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nn(-c2ccccc2)c2cc(NC(=O)c3cccc(C#N)c3)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-amine hydrochloride (1 g, 3.60 mmol, 1.00 equiv, 98%) in dichloromethane (50 mL), 3-cyanobenzoic acid (646.8 mg, 4.31 mmol, 1.20 equiv), TEA (445 mg, 4.31 mmol, 1.20 equiv), EDCI (845 mg, 4.31 mmol, 1.20 equiv). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). The collected fractions were combined and concentrated under vacuum to yield 3-cyano-N-(3-ethyl-1-phenyl-1H-indazol-6-yl)benzamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][OH:17])[CH3:13]>ClCCl.CO>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:17][CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCN(CC)CCO
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared analogously to Example 4.13.a. starting from 0.66 g (2.00 mmol) of 2-bromo-1-fluoro-4-nitrobenzene and 0.40 mL (3.00 mmol) of 2-diethylaminoethanol. Yield: 0.95 g (100% of theory); C12H17BrN2O3 (M=317.185); calc.: molecular ion peak (M+H)+: 317/319; found: molecular ion peak (M+H)+: 317/319; Rf value: 0.50 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([N-]C(C)C)(C)C.[Li+].[CH:24]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O1CCCC1>[CH:24]1([C:31](=[O:32])[CH:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: CCOC(=O)Cc1c(F)cc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of ethyl 2,4,6-trifluorophenylacetate (436 mg, 2.0 mmol) in 3 mL of tetrahydrofuran is cooled to −78° C., and lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 1.0 mL, 2.0 mmol) is added dropwise with stirring. The mixture is stirred at −78° C. for 1 h, and cycloheptanecarboxylic acid chloride (321 mg, 2.0 mmol) is added dropwise. The mixture is warmed to room temperature and acidified with 2 mL of 1.0 N hydrochloric acid. The product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 10% ethyl acetate in hexanes. Concentration provides ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate as a colorless oil (410 mg). MS: m/z 341.2 (M−H).
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3]CC.[CH2:17]([SH:19])[CH3:18].[OH-].[Na+]>CS(C)=O.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:19][CH2:17][CH3:18])[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[OH:3]
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc([N+](=O)[O-])c(P(C)(=O)O)c1

Procedure:
To a solution of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and ethanethiol (60.0 mmol) in dimethylsulfoxide (20 ml) is added a solution of sodium hydroxide (40.0 mmol) in 1 ml of water. The mixture is warmed to 60° overnight, after which it is poured into water and extracted with ether. The aqueous solution is acidified, extracted with methylene chloride, dried and evaporated to give P-methyl-2-nitro-5-ethylthiophenylphosphinic acid, which is then treated with diazomethane in methanol to give methyl P-methyl-2-nitro-5-ethylthiophenylphosphinate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g, 24.5 mmol) and benzo[d]thiazol-2-amine (5.52 g, 36.8 mmol) in DCM (80 mL) was added EDCI (9.4 g, 49.04 mmol) and DMAP (6 g, 49 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (400 mL), washed with 5% aq. HCl, water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide 8.5 g of the desired product tert-butyl 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1A): 1H NMR (300 MHz, CDCl3) δ ppm 7.83 (1H, m), 7.48 (1H, d), 7.34 (4H, m), 7.19 (1H, t), 4.91 (2H, m), 3.67 (2H, t), 2.92 (2H, t), 1.47 (9H, m). MS (ESI(+)): m/z 410 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]([CH2:18][CH2:19]Br)[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:19][CH2:18][N:12]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nn(CCBr)c(C(=O)OC)c1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCN=[N+]=[N-])c(C(=O)OC)c1OCc1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1-(2-bromoethyl)-1H-pyrazole-3,5-dicarboxylate (1.0 g, 2.52 mmol) in DMF was added sodium azide. The reaction mixture was stirred at 40° C. overnight and quenched with water (100 mL). The mixture was extracted with EtOAc four times, and the organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel using 0-30% EtOAc/hexanes gradient elution. Collection and concentration of the appropriate fractions afforded the title compound as a white solid. ES MS (M+1)=360.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OC([O-])=O)(=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in t-butyl pyrocarbonate (2.25 equivalents). After stirring at 80° C. overnight, the mixture is diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried and concentrated under vacuum to give 2-(2-t-butoxycarbonylamino-4-thiazolyl)malonic acid diethyl ester. Yield: 73.3%.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:6][N:7]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]1
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (25.00 g, 82.7 mmol), copper (1) iodide (3.14 g, 16.5 mmol), (trimethylsilyl)acetylene (81.9 mL, 579 mmol), bis(triphenylphosphine)palladium(ii) chloride (5.81 g, 8.27 mmol), and Hunig's base (115 mL, 662 mmol) was added in a sealable tube along with 100 mL THF. The reaction is sealed and heated to 80° C. under vigorous stirring for 24 h. The mixture was cooled to room temperature, filtered and evaporated. The resulting oil was purified using Biotage (75 L, 0-50% EtOAc/hexanes) affording methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate as a transparent brown oil. MS (ESI) m/z: Calculated: 319.1; Observed: 320.1 (M++1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C([O-])(=O)C.[Na+:13]>C(O)(=O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Na+:13]
Reactant: O=C(O)/C=C/C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])/C=C/C(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sulpher sodium nitrate and solid acetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:14][NH2:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Si]([O:23][CH2:24]C=O)(C(C)(C)C)(C)C.Cl>>[NH2:15][CH2:14][C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7][N:2]([CH2:1][CH2:24][OH:23])[CH2:3][CH2:4]1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Agent: Cl
Product: NCC1(c2ccccc2)CCN(CCO)CC1

Procedure:
The title material was prepared as described for the synthesis of (1-methyl-4-phenylpiperidin-4-yl)methanamine (Example B above) in using 2-(tert-butyldimethylsilyloxy)acetaldehyde and by doing an acidic work-up (HCl 5N) after the reductive amination to remove the protecting group. LC/MS (M+H)+: 235. HPLC ret. time (Condition A): 0.143 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (34 mg, 0.094 mmol) was added DCM (0.9 mL), triethylamine (26 μl, 0.188 mmol), and methanesulfonyl chloride (11 μl, 0.141 mmol) before it was stirred at ambient T for 1 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 5 N NaOH (aqueous), washed 3 times with 75 mL of 5 N NaOH (aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to the title compound. MS (ESI) m/z: Calculated: 517.1; Observed: 518.0 (M++1).