Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:2][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Nc1cc(C(=O)O)ccc1CN1CCCC1
Yield: 85 %

Procedure:
4-Bromomethyl-3-nitrobenzoic acid (10 g) is dissolved in dichloromethane (100 ml) and thereto is added dropwise pyrrolidine (8 g) with stirring under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Dichloromethane is distilled off under reduced pressure, and the residue is dissolved in conc. hydrochloric acid (40 ml) and thereto is added water (10 ml) with stirring under ice cooling and further is added tin (5.4 g), and the mixture is stirred under ice cooling for 1.5 hour. The reaction mixture is neutralized with 10N aqueous sodium hydroxide solution, and the catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in water and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and concentrated into dryness under reduced pressure to give 3-amino-4-(1-pyrrolidinylmethyl)benzoic acid (7.2 g).
Reaction SMILES: BrC[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C-:10]#[N:11].[Na+].O.C(O[CH2:18][CH3:19])(=O)C>C1(C)C=CC=CC=1>[C:8]([CH2:7][CH2:6][C:5]1[SH:4]([C:10]#[N:11])[CH:3]=[CH:18][CH:19]=1)#[N:9]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccsc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCCC1=CC=C[SH]1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
2-Bromomethyl-3-cyanothiophene (2.746 g) was dissolved in toluene (40 ml), followed by the addition of a solution of sodium cyanide (2.002 g)/water (15 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow solid (823 mg, yield; 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a solution of 50 mg (0.25 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 81 mg of TBTU (0.25 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 89 mg (0.25 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 56 mg light yellow amorphous material (38%). MS: 530.1 (M).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.Cl.O1CCOCC1>>[ClH:29].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]4)[CH2:11][CH2:10]2)=[CH:32][CH:31]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: NCc1ccccc1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(Cl)cc4)CC3)cccc2n1
Yield: 56 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 4-chlorobenzyl bromide (66 mg; 0.32 mmol) via Method BB to a solid, which was stirred in the presence of 4M HCl in dioxane (4 eq). Solids were filtered and rinsed once with ether to give title compound. (66 mg; 56% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 11.3 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.7 (m, 4H), 7.52 (d, J=6.8 Hz, 2H), 7.02 (m, 2H), 4.66 (br s, 3H), 4.26 (d, J=4.8 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.34 (br d, J=11.6 Hz, 2H), 2.87 (m, 2H), 2.2 (m, 1H), 1.81 (m, 4H). MS m/z (ESI) 398 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(-c2cc(C(=O)O)c(C)cc2C2CCC2)n[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)n[nH]1
Temperature: 30 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound 445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and 4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 30° C., and then diluted with 40 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (59.0% CH3CN up to 73.0% in 6 min, up to 100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 150 mg (72%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+.
Reaction SMILES: F[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](C1C=CC(OCC2C=CC(C(C3C=C(C=CC=3)C#N)C)=CC=2)=C(CCC)C=1O)(=O)C>>[OH:18][C:11]1[C:10]([CH2:19][CH2:20][CH3:21])=[C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)[CH:25]=3)[CH3:35])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[C:15](=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccc(C(C)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(C)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described for 1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone employing 3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ethyl}-benzonitrile. The title compound is obtained (12.5 mg, 45%) as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.00 (s, 1H), 7.75-7.85 (m, 2H), 7.35-7.54 (m, 6H), 6.73 (d, 1H), 5.23 (s, 2H), 4.32 (m, 1H), 2.55-2.60 (m, 5H), 1.66 (d, 3H), 1.46-1.50 (m, 2H), 0.87 (t, 3H). LCMS M+1 457.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][CH2:7][CH2:6][N:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]([CH:9]1[CH2:8][CH2:7][CH2:6][N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:3])[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)CCCN1c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)CCCN1c1ccccc1
Reaction time: 1.5 h

Procedure:
Under inert atmosphere, to a stirred solution of NaH (2.5 mg, 0.05 mmol) in 0.10 ml anhydrous DMF at 0° C., was added a solution of compound of Example 8 (0.02 g, 0.05 mmol) in 0.20 ml anhydrous DMF. After 1.5 h at 0° C., benzyl bromide (7 μl, 0.05 mmol) was added to the reaction mixture. This mixture was stirred for 2 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt 50/50 as the eluant, yielding 0.016 g (71%, purity 92%) of the desired product.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:33]2[C:28](=[CH:29][C:30]([F:51])=[C:31](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[N:32]=2)[C:27](=[O:52])[C:26]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:25]1.O>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:31]2[N:32]=[C:33]3[C:28]([C:27](=[O:52])[C:26]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:25][N:24]3[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])=[CH:29][C:30]=2[F:51])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OP(=O)(Oc3ccccc3)Oc3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 75.9 %

Procedure:
In 2 ml of ethanol was suspended 64 mg of 3-aminopyrrolidine dihydrochloride, and 130 mg of triethylamine was added to the resulting suspension to form a solution. Subsequently, 200 mg of ethyl 1-(2,4-difluorophenyl)-7-diphenoxyphosphinyloxy-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the solution, and the resulting mixture was subjected to reaction at room temperature of 1 hour. Subsequently, 3 ml of water was added to the reaction mixture, and the crystals thus deposited were collected and washed with 3 ml of water to obtain 110 mg (yield 75.9%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[CH:7][N:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:19](=[O:21])[CH3:20])[N:6]=1
Reactant: COC(=O)Cc1ncc2ccccn12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1nc(C(C)=O)c2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of imidazo[1,5-a]pyridin-3-yl-acetic acid methyl ester (1.38 g, 7.26 mmol) in CH2Cl2 (50 mL) was added to a suspension of AlCl3 (2.9 g, 21.77 mmol) in CH2Cl2 (115 mL) and the mixture was stirred at RT for 30 min under nitrogen atmosphere. Acetyl chloride (1.55 mL, 21.77 mmol) was subsequently added dropwise and the mixture was further stirred overnight. AlCl3 (1.94 g, 14.51 mmol) and 15 min later acetyl chloride (1.04 mL, 14.51 mmol) were added and stirring was continued overnight to complete the reaction. The reaction mixture was cooled with at 0° C. and carefully quenched by cautious addition of MeOH (35 mL). Solvents were evaporated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 94:6). TLC, Rf (CH2Cl2/MeOH 9:1)=0.60; MS (UPLC/MS): 233.1 [M+H]+, 255.1 [M+Na]+, 487.1 [2M+Na]+; tR (HPLC conditions f): 1.27 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][CH:22]([CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[CH3:38])=[O:24]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:35]1[CH2:36][CH2:37][CH:32]([C:30]2[CH:29]=[CH:28][C:27]([CH3:38])=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:39])[CH:31]=2)[CH2:33][CH2:34]1)(=[O:20])[CH3:19]
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Reactant: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3ccc(C)c(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure G and Scheme AI using 1-(3-{[(1S)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 512.9 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])=[CH:41][C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:40]1[CH:39]=[CH:38][C:37]2[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[N:34][S:35][C:36]=2[CH:41]=1)(=[O:44])=[O:43])([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCN)nsc2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc2c1
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 4-iodobenzoic acid (181 mg, 0.7 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (115 μL, 0.8 mmol) and 4-methylmorpholine (160 μL, 1.5 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-6-sulfonamide (238 mg, 0.7 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 1:1 ethyl acetate:hexanes provided N-(3-(6-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (252 mg). 1H NMR (300 MZh, CDCl3): 8.47 (d, 1H), 7.96 (dd, 1H), 7.86 (d, 1H), 7.82 (d, 2H), 7.60 (d, 2H), 7.37 (t, 1H), 6.19 (br s, 1H), 4.98 (s, 1H), 3.75 (t, 2H), 3.60 (dd, 2H), 2.02 (q, 2H), 1.29 ppm (s, 9H). 13C NMR (CDCl3): 167.25, 159.79, 154.96, 139.87, 138.01, 134.16, 128.91, 126.28, 121.54, 121.19, 98.76, 55.46, 43.08, 40.33, 37.32, 30.66, 30.06. MW=572 confirmed by LC-MS, tr=14.28 min (Method Y) MH+=573.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O[C:13](=O)[C:14]1[CH:19]=CC(Cl)=N[CH:15]=1)C.C([Mg]Cl)C(C)C>>[CH2:13]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][N:4]=1)[CH:14]([CH3:19])[CH3:15]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C(O)c1cccnc1
Agent: CC(C)C[Mg]Cl
Product: CC(C)Cc1ccc(C(=O)O)cn1

Procedure:
6-Isobutyl-nicotinic acid is prepared in analogy to Nicotinic acid 2 from commercially available 6-chloronicotinic acid ethyl ester and isobutylmagnesium chloride; LC-MS: tR=0.52 min, [M+1]+=180.30.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][O:18][CH3:19])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:20]([OH:22])[OH:21]>>[CH3:19][O:18][CH2:17][O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:20]([OH:22])[OH:21]
Reactant: COCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: OBO
Product: COCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 8 g (24.4 mmol) of 3-bromo-2-methoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 5.5 g (77%) of the expected boronic acid are obtained, with a melting point of 133-4° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[C:1]1([S:7][CH2:8][CH2:9][S:10][CH2:11][CH:13]([OH:15])[CH2:14][S:10][CH2:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCSc1ccccc1
Reactant: ClCC1CO1
Product: OC(CSCCSc1ccccc1)CSCCSc1ccccc1

Procedure:
An excess of 2-(phenylthio)ethanethiol is reacted with epichlorohydrin to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol. In the final step, the 1,3-bis(2-(phenylthio)ethylthio)propan-2-ol is reacted with a acryloyl chloride in the presence of a tertiary alkyl amine and dimethylaminopyridine to form 1,3-bis(2-(phenylthio)ethylthio)propan-2-yl acrylate.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1>[Cl:11][C:8]1[N:7]=[C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]2=[N:4][CH:3]=[C:2]([C:25]#[N:26])[N:10]2[N:9]=1
Reactant: N#C[Cu]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(Br)cnc12
Solvent: CN1CCCC1=O
Product: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
To an oven dried 500 ml round bottom flask was added 7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (12.5 g, 31.5 mmol) and copper(I) cyanide (9.0 g, 100 mmol). The flask was caped under nitrogen and NMP (250 mL) was added. The mixture stirred 5 min at 25° C. and the flask was evacuated and back-filled with nitrogen 3×. The reaction stirred at 135° C. (oil bath) 21 hr. The reaction cooled to 25° C., diluted with ethyl acetate (500 ml) and filter through celite bed. The bed was washed with EtOAc 3×100 ml and the filtrate washed with water 1×300 ml and brine 3×150 ml. The organics dried with sodium sulphate and remove solvent. The material was crystallized from IPA and filtered to afford 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (11 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([O:14]CC)=O)=[N:11][C:7]=3[C:6]=2[CH:21]=1.[NH3:23]>CO>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([NH2:23])=[O:14])=[N:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: N
Solvent: CO
Product: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 100 %

Procedure:
A solution of ethyl 9-bromo-8-fluoro-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (80 mg, 0.22 mmol) in methanolic ammonia (10 mL of a 7M ammonia solution in methanol) was warmed to 40° C. for 3d in a pressure tube. Evaporation of the reaction mixture in vacuo furnished the title compound (77 mg, 0.22 mmol, 100%) as a colorless solid: 1H NMR (500 MHz, d4-methanol) δ 1.62-1.69 (m, 2H), 2.92-3.01 (m, 2H), 3.45-3.50 (m, 1H), 3.65-3.72 (m, 1H), 6.97-7.02 (m, 1H), 8.42-8.50 (m, 1H); M+1=336/338.
Reaction SMILES: C([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)(C)C.[CH2:9]([Li])[CH2:10][CH2:11]C.[B:14](OCCCC)([O:20]CCCC)[O:15]CCCC>C1COCC1>[CH:10]([N:5]1[C:4]([B:14]([OH:20])[OH:15])=[CH:8][CH:7]=[N:6]1)([CH3:11])[CH3:9]
Reactant: [Li]CCCC
Reactant: CC(C)c1cc[nH]n1
Reactant: CCCCOB(OCCCC)OCCCC
Solvent: C1CCOC1
Product: CC(C)n1nccc1B(O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of isopropylpyrazole (5.0 g, 45.5 mmol) in THF (100 mL) was added n-butyl lithium (31 mL, 50 mmol, 1.6 M in hexane) at −78° C. The mixture was kept stirring at the same temperature for 30 min. and was allowed to warm to 0° C. and stirred for another 30 min. Before adding tri-n-butyl borate (12.6 g, 55 mmol) as one portion, the reaction mixture was cooled to −78° C. After addition, the mixture was stirred at −78° C. for 1 h. and was allowed to warm to r.t. slowly and stirred overnight. The reaction mixture was quenched by saturated ammonium chloride. The organic phase was separated and the aqueous phase was extracted with ethyl ether (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate. Solvent was removed to afford 1-isopropyl-1H-pyrazole-5-boronic acid as a viscous oil (5.7 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15](=O)[CH3:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15](=[N:19][OH:20])[CH3:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=NO)c1cncc(C#Cc2ccccc2)c1

Procedure:
Prepared in the same manner as described in EXAMPLE 6, using 1-(5-phenylethynyl-pyridin-3-yl)-ethanone, (prepared as described in EXAMPLE 166), (0.22 g, 0.97 mmol), hydroxylamine hydrochloride (0.54 g, 7.78 mmol) and potassium carbonate (0.67 g, 4.86 mmol) to give the free base of the title compound. Convert the free base to the hydrochloride salt as described in EXAMPLE 163 to give the title compound (0.112 g, 42%).