Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH:9]([CH:22]1[NH:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClCCl.Cl[CH2:43][C:44](Cl)=[O:45]>O>[CH:9]([CH:22]1[N:27]2[C@@H:26]([CH2:28][O:29][CH2:43][C:44]2=[O:45])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N[C@@H](CO)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N2C(=O)COC[C@H]2C1
Reaction time: 1 h

Procedure:
Potassium carbonate (81.3 mg) was added to a mixture of [(2R)-6-benzhydryl-4-(2-methoxybenzyl)piperazin-2-yl]methanol dihydrochloride (48.0 mg) in a mixed solvent of dichloromethane and water. Chloroacetyl chloride was. added to the mixture below 5° C. and the whole was stirred for 1 hour. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue was dissolved into tert-butanol (4 ml) and potassium tert-butoxide (22.0 mg) was added to the mixture. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative TLC (15 PLC plate 20×20 cm, silica gel 60 F254, 1 mm, Merck) with a mixture of hexane and ethyl acetate as an eluent to give (9aR)-6-benzhydryl-8-(2-methoxybenzyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-one (30 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]#[N:16])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 24.5 %

Procedure:
3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile (20 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-cyanophenylboronic acid (50.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]2[CH3:22])=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Compound 8 was dissolved in anhydrous DMF (Aldrich) in a 500 mL 1-neck round bottom flask. Anhydrous potassium carbonate (EM Science) was added and the mixture was stirred for 15 min. After addition of iodomethane (Aldrich), the mixture was stirred at room temperature overnight, after which it was concentrated and partitioned between CH2Cl2 and aq. sodium thiosulfate. The CH2Cl2 layer was rinsed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to 19.30 g crude 9 (brownish solid). 1H NMR spectrum was satisfactory; however, TLC (MeOH:DCM 1:9) shows small amounts of lower polarity impurities and some high polarity impurities (possibly largely inorganic). Attempts to purify via re-precipitation from THF/water or CH2Cl2/hexane were unsatisfactory. Chromatography on a silica gel plug (gradient 1-2-4-6-10% methanol in CH2Cl2) provided purified product (17.93 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.N12CCCN=C1CCCCC2>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH:6]=1
Reactant: COC(=O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Yield: 0 %

Procedure:
A solution of benzyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (5.25 g, 18.1 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.71 mL, 18.1 mol) in DMF (120 mL) was stirred at room temperature. After 3 d the reaction was diluted with water and extracted with ether (4×). The organic washes were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 30% ethyl acetate:hexanes to give the title compound (2.44 g). MS: m/z=290.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.30-7.25 (m, 5H), 5.5 (brs, 1H), 5.2 (s, 2H), 4.0 (brs, 2H), 3.7 (s, 3H), 3.6 (brs, 2H), 3.0 (s, 2H), 2.2 (brs, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=[C:5]2[CH3:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.N1CCCCC1.CCOC(C)=O>O1CCOCC1.[Cu]I>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[C:5]4[CH3:19])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(N2CCC(C)CC2)nc2ccc(I)cc12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 293 mg (0.8 mmol) of 6-iodo-4-methyl-2-(4-methylpiperidin-1-yl)quinoline, 184 mg (0.8 mmol, 93% purity) 5-(4-chlorophenyl)-2-ethynylpyridine, and 158 μL (1.6 mmol) of piperidine in 4 mL of 1,4-dioxane is evacuated three times and gassed with argon. After the addition of 3 mg (0.016 mmol) of CuI and 13 mg (0.016 mmol) of PdCl2(dppf)-DCM complex, the reaction mixture is stirred for 4 hours at RT. It is combined with 10 mL of EtOAc, and the precipitate is filtered off, washed with a little EtOAc and MeOH, and dried in the air. Yield: 240 mg (66% of theoretical); C29H26ClN3 (M=451.990); calc.: molpeak (M+H)+: 452/454 (Cl); found: molpeak (M+H)+: 452/454 (Cl); HPLC-MS: 6.1 min (method B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a stirred solution of 15.0 g (0.063 mole) of 2,5-dimethoxybenzenesulfonyl chloride in 150 mL of tetrahydrofuran was added dropwise 80 mL of ammonia (28% aqueous solution). After complete addition the mixture was allowed to stir for 1.75 hours at room temperature. Upon standing the mixture separated into two phases. The organic phase was removed from the aqueous phase and was evaporated under reduced pressure to leave a solid residue. This residue was recrystallized from hot water (125 mL) and ethanol (40 mL) to yield 13.1 g of 2,5-dimethoxyphenylsulfonamide (mp 146.5-148.5).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][N:3]=1.OC1C=CC(C(O)=O)=CN=1.[NH2:21][C:22]1[C:23](=[O:36])[N:24]([CH2:33][CH2:34][CH3:35])[C:25](=[O:32])[N:26]([CH2:29][CH2:30][CH3:31])[C:27]=1[NH2:28].Cl>C(Cl)Cl.N1C=CC=CC=1.[OH-].[Na+].O>[CH2:33]([N:24]1[C:23](=[O:36])[C:22]2[NH:21][C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[N:28][C:27]=2[N:26]([CH2:29][CH2:30][CH3:31])[C:25]1=[O:32])[CH2:34][CH3:35]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: O=C(O)c1ccc(O)nc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc2n(CCC)c1=O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
6-Chloronicotinoyl chloride, prepared from 6-hydroxynicotinic acid (1.44 g, 10.4 mmol), in CH2Cl2 (20 ml) was added dropwise to a solution of 5,6-diamino-1,3-dipropyluracil (1.81 g, 8 mmol) in dry pyridine (8.2 ml) maintained at 5° C. The reaction was warmed to room temperature and stirred for an additional 3 hours. Water (50 ml) was added to quench the reaction. The solvent was evaporated to afford a dark colored oil. The oil was refluxed for 2 h in 2N NaOH (20 ml). After cooling, the pH was carefully adjusted to 7 with concentrated HCl. A solid formed and was collected and washed with water (20 ml), ether (20 ml) and chloroform (20 ml) to provide an off-white solid (1.9 g). The product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH:5]([N:13]2[CH2:18][CH2:17][CH:16](O)/[C:15](=[CH:20]/[C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)/[CH2:14]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[CH2:3][CH2:2]1.[C:27]([OH:30])(=[S:29])[CH3:28].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:27]([S:29][CH:16]1[CH2:17][CH2:18][N:13]([CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:26])[CH2:14]/[C:15]/1=[CH:20]\[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)(=[O:30])[CH3:28]
Reactant: CC(O)=S
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)/C(=C/c2ccco2)C1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(furan-2-yl)methylidene]piperidin-4-ol (2.30 g) in toluene (50 ml) were added thioacetic acid (0.92 ml) and N,N-dimethylformamide dineopentyl acetal (3.61 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19 to 1:9) as the eluent to afford the title compound (0.58 g, yield: 22%) as an orange-coloured oil.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[CH:16]([CH3:18])[CH3:17].[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:15]([NH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[C@H](NCC(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (5.23 mmol, 1 eq) in MeOH (50 ml) there were added first acetic acid (2 drops) and then, at 0° C., isobutyraldehyde (0.47 ml, 5.23 mmol, 1 eq), and stirring was carried out for 1 h at RT. The reaction mixture was cooled to 0° C. again, NaCNBH3 (821 mg, 13.07 mmol, 2.5 eq) was added, and stirring was carried out for a further 30 min at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated, and the residue was taken up in water (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic phases were washed with sat. NaCl solution (2×60 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (Alox neutral, 3% MeOH in dichloromethane), the desired product was obtained. Yield: 65% (0.850 g, 33.44 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.CO.Cl.[NH2:16][OH:17]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[N:16][OH:17])[CH:5]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 ml round flask, 2.31 g (14.1 mmol) of 3-formyl-benzoic acid methyl ester are dissolved in 25 ml of water and 45 ml of methanol and cooled to 0° C. After reaching this temperature, 980 mg (14.1 mmol) of hydroxylamine hydrochloride are added and the mixture stirred for 1 h under warming to room temperature. Then, the mixture is poured onto water and extracted twice with ethyl acetate. The organic layers are dried with brine and over Na2SO4 and concentrated. This yields the title compound as a white solid which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 179.9
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](O)=[O:15]>O1CCCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCc1ccccc1F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of borane dimethylsulfide complex (2M in THF, 27.6 mL) was added dropwise to a solution of 3-(2-fluorophenyl)propanoic acid (3.09 g) in tetrahydrofuran (25 mL) and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with methanol and, when bubbling had ceased, evaporated. Purification was by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 2.72 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)=[O:18]>CC(O)C.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(S(N)(=O)=O)c2)c(N)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 3-[3-amino-6-chloro-1-(ethoxycarbonyl)indole-2-carbonyl]benzenesulfonamide (step 1). m.p.: 125-127° C. (2-propanol/toluene)
Reaction SMILES: [C:1]([N:5]1[CH2:42][CH2:41][CH2:40][CH2:39][C:8]2[C:9]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27](OCC)=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:43])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].[NH4+].[Cl-]>C1COCC1.C(O)C>[C:1]([N:5]1[CH2:42][CH2:41][CH2:40][CH2:39][C:8]2[C:9]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@@H:21]5[CH2:27][OH:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1[C@@H]1OC(C)(C)O[C@@H]1CO)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 680 mg of 21f in 20 ml of THF and 0.5 ml of ethanol was added dropwise 0.56 ml of a 2M solution of LiBH4 in THF. The reaction was stirred for 3 hr. The reaction was poured onto 5% NH4Cl solution, and the product was extracted into ethylacetate. The extract was dried and concentrated to provide 620 mg of product 21g which was used as is in the next step; Rf (Hept./ethyl acetate 1/1) 0.21. NMR (CDCl3) δ 7.35, 7.10, and 6.92 (3×m, 3, thienyl-H), 6.70 and 7.33 (2×s, 2, Ar—H); 5.10 (bd, 1, CHO), 4.65 (bm, 1, CH), 3.50-3.90 (bm, 6, CHO+CH2O+CH+CH2), 3.82 (s, 3, OCH3), 2.90+3.12 (2×bm, 2, CH2) 2.50 (b.m, 2, CH2) 1.60-2.05 (bm, 4, 2×CH2) 1.42 and 1.25 (2×s, 6, 2×CH3) 1.56 (s, 9, tertC4H9).
Reaction SMILES: BrBr.[Cl:3][C:4]1[C:5]([NH:10][NH:11][C:12]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=S)=[N:6][CH:7]=[CH:8][N:9]=1.[OH-].[NH4+]>C(O)(=O)C.O.C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:5]2[N:6]([C:12]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[N:11][N:10]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)NC(=S)NNc1nccnc1Cl
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1nnc2c(Cl)nccn12
Reaction time: 1.33 h
Yield: 48.6 %

Procedure:
A solution of bromine (653 μl, 12.74 mmol) in acetic acid (9 mL) was added to a solution of ethyl 2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (3.523 g, 14.40 mmol) in acetic acid (30 mL) at room temperature and stirred for a further 80 minutes. The mixture was cooled in an ice-bath while 15% ammonium hydroxide solution (180 mL) was added to the reaction mixture, ensuring the reaction temperature remained below 30° C. The mixture was diluted with water (50 mL) and chloroform (120 mL) and filtered. The cake was washed with chloroform (50 mL) and dried under high vacuum at 50° C. to yield ethyl 8-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-ylcarbamate (1.69 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH3:25]
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Reactant: CCNCC
Product: CCN(CC)c1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12

Procedure:
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine and excess of diethylamine in alcohol (1 mL) in sealed tube was heated at 120° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N,N-diethyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine. 1H NMR (CDCl3): δ 8.61 (d, 2H, J=6.0 Hz), 7.61–7.66 (m, 2H), 7.22–7.34 (m, 4H), 7.09 (t, 2H, J=8.7 Hz), 6.32 (d, 1H, J=6.1 Hz), 3.64 (q, 4H, J=7.0 Hz), 1.26 (t, 6H, J=7 Hz). MS (ES+ve): 362 (25, M+2), 361 (100, M+1).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([C:28]3[N:29]=[CH:30][NH:31][CH:32]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[NH:31]1[CH:32]=[C:28]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[CH:18]=3)[NH:10][CH:11]=2)[N:29]=[CH:30]1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(-c2c[nH]cn2)cn3S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(-c2cnc3[nH]cc(-c4c[nH]cn4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To 17 (50 mg, 0.113 mmol) in EtOH (2.5 mL) was added 10% aq. NaOH (1.3 mL) and the reaction mixture was stirred at room temperature for 2 h then at 85° C. for 10 rain. It was cooled and poured onto water (3 mL) and extracted with ethyl acetate (4×5 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give product 18 as a white solid (9.0 mg, 26%); 1H NMR (400 MHz, CDCl3+4 drops CD3OD) δ 2.97 (s, 6H), 6.83 (d, J=8.9 Hz, 2H), 7.27 (d, J=1.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 7.67 (d, J=1.0 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H); MS (CI) m/z 304.1 (MH), 345.1 (M+MeCN).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([OH:26])=[O:25])=[CH:15]1.C(I)CC>O1CCCC1>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]([CH2:1][CH2:2][CH3:3])[C:24]([OH:26])=[O:25])=[CH:15]1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: [Li]CCCC
Solvent: CCCI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC(C(=O)O)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere, butyl lithium (1.6M, 10 mL, 16 mmol) was added at −78° C. to a solution of diisopropylamine (2.22 mL, 15.84 mmol) in anhydrous tetrahydrofurane. After 25 minutes, a solution of 1-methyl-3-indoleacetic acid (1 g, 5.28 mmol) in tetrahydrofurane (20 mL) was slowly added at −78° C., followed by the addition of propyliodide (1 mL, 10 mmol) after 45 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with water (20 mL) and washed with diethyl ether (20 mL). The organic layer was acidified with hydrochloric acid aqueous solution 1N to pH 3 and extracted with dichloromethane (3×10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired acid (12a) as a brown solid without further purification (1.22 g, 5.28 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])=[CH:26][CH:25]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)CCc1ccc(N)cc1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 553.9 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (247 mg, 1.5 mmol) to afford the desired product (2284 mg, 55%) as a yellow solid: ESI MS m/z 412 [C21H22BrN3O+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28]1>>[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32]2)[CH2:29][CH2:28]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C1CC1)[C@@H]1CCCNC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N(C)C4CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-cyclopropyl-N-methylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.13-0.61 (m, 4 H) 1.38-1.64 (m, 2 H) 1.64-2.09 (m, 3 H) 2.15-2.41 (m, 3 H) 2.43 (s, 3 H) 2.55-2.86 (m, 2 H) 3.04 (br. s., 1 H) 3.49-3.87 (m, 1 H) 4.33-4.77 (m, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.81 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.02 Hz, 1 H) 8.13 (s, 1H) 8.40 (d, J=7.33 Hz, 1 H) 8.53 (d, J=1.77 Hz, 1 H); ESI-MS m/z [M+H]+ 457.3.