Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1)[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: Cc1cc(Oc2ccnc3cc(I)sc23)ccc1N
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)c(C)c3)c2s1

Procedure:
Prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)-2-methylbenzenamine (0.250 g, 0.556 mmol), and N,N-diethylprop-2-yn-1-amine (0.0680 g, 0.612 mmol), according to the procedure for Example 6, Step B. The crude was purified by Biotage 40S (EtOAc). The product was an orange oil (116 mg, 39%). LRMS (ESI pos) m/e 366 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15]C)=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]=2[CH:14]=1)(=[O:3])[CH3:2].B(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:15])=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1C(C)=O)C(C)CCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)OCCC2C
Temperature: 25 °C
Yield: 65.9 %

Procedure:
The product of step (d) (57.4 g) in dry methylene chloride (500 ml) was treated with boron trichloride (61 g) in dry methylene chloride (150 ml) at -70° C. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature during 1 hour. The reaction mixture was poured into water and the methylene chloride layer was separated, washed with water and dried. Evaporation of the solvent left 55.7 g of crude product; this was dissolved in ether and extracted several times with a sodium hydroxide solution. The basic extracts were acidified and the precipitated product extracted with ether, which was washed with water and dried. Evaporation of the solvent gave 35.4 g of product mp 91°-96°. A recrystallisation from ethanol gave the title compound, mp 101°-105°.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([O-:12])=O.[K+].[Cl-].[Mg+2].[Cl-].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1C(Cl)=O>C(#N)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.8 %

Procedure:
Triethylamine (11.7 mL, 84.3 mmol) was added dropwise to a suspension of potassium ethyl malonate (13.4 g, 78.5 mmol) in acetonitrile (80 mL) at 10° C., followed by portionwise addition of anhydrous magnesium chloride (9.12 g, 95.8 mmol). The reaction mixture was warmed to room temperature and stirred for 2.5 h. The resulting white slurry was cooled to 0° C. and furan-2-carbonyl chloride (5.0 g, 38.3 mmol) in acetonitrile (20 mL) was added dropwise over a period of 20 min. The mixture was allowed to stir at ambient temperature overnight. The solvent was evaporated in vacuo and the residue was azeotroped with toluene (10 mL) then dissolved in toluene, cooled to between 0 and 5° C. and acidified with 13% aqueous hydrochloric acid (50 mL). After stirring for 15 min the aqueous phase was separated and the organic phase was washed with 13% aqueous hydrochloric acid (2×50 mL) followed by water (2×25 mL) and concentrated in vacuo to afford the crude compound. Purification by flash column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent afforded ethyl 3-(2-furyl)-3-oxo-propanoate (5.01 g, 72%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34]/[CH:35]=[CH:36]/[CH:37]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:37](/[CH:36]=[CH:35]/[C:34]#[C:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C/C=C/C#Cc1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C#Cc2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction was carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynal as described in Reference example 48 to obtain the title compound, a major product as an oil in a yield of 70%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CC[C@@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 60 mg of (S)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester in N,N-dimethylformamide (2.0 mL) is added 66 mg of 3-bromomethyl-4,6-dimethyl-1,2-benzoisothiazole and 36 mg potassium carbonate at room temperature. The mixture is heated to 60° C. for 2.5 h. Then 50 mL of water is added and the product is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 80 mg (82%) of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH3:12])[CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH3:12])[CH2:6][CH2:5]2)=[O:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCc2cc(N)ccc2C1
Product: COc1cc(C(=O)Nc2ccc3c(c2)CCN(C)C3)cc(OC)c1OC

Procedure:
6-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3,4,5-trimethoxybenzoyl chloride as in Example 16 to yield 6-(3,4,5-trimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline. It was recovered as the HCl salt; m.p. 233.5°-235° C. after purification in methanol.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[N:14]1[CH2:15][CH2:16][N:17]([C:2]2[C:3](=[O:13])[C:4]3[C:9]([C:10](=[O:12])[C:11]=2[OH:1])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:18][CH2:19]1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Solvent: CCO
Product: O=C1C(O)=C(N2CCN(c3nc4ccccc4o3)CC2)C(=O)c2ccccc21
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A mixture of 3.48 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.03 g of 2-(1-piperazinyl)benzoxazole and 200 ml of absolute ethanol was stirred 18 hours and then filtered. The filtrate was concentrated to dryness and the residue flash chromatographed, eluting with dichloromethane, then 1% methanol in dichloromethane. The desired fraction was evaporated, then recrystallized twice from dichloromethane/ethanol, giving 533 mg of the desired product, mp 190°C. (dec.).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[H][H].[Pd]>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Yield: 56 %

Procedure:
Following the general procedure-1, Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (90 mg) obtained from intermediate 44 (200 mg, 0.51 mmol) and Tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.511 mmol). Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and added Pd/C (90 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the crude. Crude was triturated with Petether and EtOAc (1:1) to obtain the titled compound (50 mg) as an off-white solid. M.P.: 161-164° C. 1H-NMR (δ ppm, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J 8.4, 2H), 7.63 (d, J 1.5, 1H), 7.53 (d, J 8.4, 1H), 7.26-7.20 (m, 1H), 4.34-4.20 (m, 2H), 2.90-2.75 (m, 3H), 1.93-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH:26]([F:28])[F:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH:14]=1)C1C=CC=CC=1.C(S)C.B(F)(F)F.O(CC)CC>C(Cl)Cl.CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:29])[N:11]([CH:26]([F:28])[F:27])[CH:12]=2)=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=c1c(OCc2ccccc2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)cn1C(F)F
Agent: FB(F)F
Solvent: CCS
Solvent: CO
Solvent: ClCCl
Product: O=c1c(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)cn1C(F)F
Yield: 48 %

Procedure:
To a solution of crude 3-(benzyloxy)-5-[4-chloro-3-(trifluoromethyl)phenyl]-1-(difluoromethyl)pyridin-2(1H)-one (58 mg) in CH2Cl2 (1 mL) was added ethanethiol (0.050 mL, 0.675 mmol) then BF3—OEt2 (0.086 mL, 0.675 mmol) at RT. After 3 h the mixture was diluted with MeOH and concentrated. The residue was taken up in DMSO:H2O and purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-70% CH3CN/water over 20 min at 20 mL/min) to give the title compound (22 mg, 48%) as an off-white solid. 1H NMR (500 MHz, d6-DMSO): δ 10.12 (s, 1 H); 8.09-7.90 (m, 3 H); 7.82-7.75 (m, 2 H); 7.25 (d, J=2.3 Hz, 1 H). HRMS (ES) calc (M+H)+=340.0158, found 340.0165.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:17][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(CO)c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CN1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 58 %

Procedure:
To a solution of Intermediate 2 (0.60 g, 1.88 mmol) in anhydrous DMF (20 ml), at 0° C., was added sodium hydride (0.113 g of a 60% dispersion in oil, 2.81 mmol) and the mixture stirred for 0.2 h, before adding methyl iodide (0.399 g, 2.81 mmol), dropwise. The mixture was warmed to room temperature, stirred for 2 h, and then partitioned between water and ethyl acetate. The organic phase was separated and washed with water (×2) and brine (×1). After drying (MgSO4), the solvent was removed in vacuo and the crude product chromatographed through silica gel eluting with ethyl acetate/hexane (1:1) to give the desired methyl ether (0.365 g, 60%), δ(250 MHz, CDCl3) 1.44 (9H, s, (Me)3), 2.26-2.78 (6H, m, 3 of CH2), 3.02-3.16 (1H, m, CH), 3.31 (3H, s, OMe). 3.34-3.40 (4H, m, 2 of CH2), 3.53-3.69 (2H, m, CH2), 7.19-7.34 (5H, m, Ar-H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].[N:35](C(OCC)=O)=NC(OCC)=O.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[NH2:35][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Triphenylphosphine (14.3 g) was added to a THF (190 ml) solution containing tert-butyl ((1S,2S)-2-hydroxycyclohexyl)carbamate (10.0 g), followed by ice cooling. Diethyl azodicarboxylate (40% in toluene) (24.3 g) and DPPA (15.3 g) were added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was left overnight. The solvent was distilled away under reduced pressure. Water was added and then a 20% sodium hydroxide aqueous solution was added. Then, the organic layers were collected. Water (30 ml) was added to the obtained organic layers, followed by heating to 60° C. A THF (40 ml) solution containing triphenylphosphine (14.3 g) was added dropwise, followed by reflux for 2.5 hours. The solvent was distilled away under ordinary pressure. Toluene was added and the pH was adjusted with 3M hydrochloric acid to pH=1 or less. Then, the resulting aqueous layers were collected, ethyl acetate was added, and the pH was adjusted with a 20% sodium hydroxide aqueous solution to pH 12. The organic layers were collected and dried over anhydrous sodium sulfate. Light yellow oily matter of tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (5.24 g) was thus obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])=[CH:3][C:4]#[N:5].CC1(C)[O:13][C:12](=O)[CH:11]=[C:10]([CH3:15])O1>CCOC(C)=O>[CH3:6][C:2]1[NH:1][C:10]([CH3:15])=[CH:11][C:12](=[O:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(N)=CC#N
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c(C#N)c(C)[nH]1
Temperature: 130 °C
Yield: 19.4 %

Procedure:
A 250 mL round bottom flask was charged with 3-aminobut-2-enenitrile (10.00 g, 122 mmol), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (32.4 mL, 244 mmol), and a magnetic stir bar. The flask was equipped with a reflux condenser and a CaCl2 tube and the reaction mixture was heated at 130° C. for 1 h. The reaction was allowed to cool room temperature and was diluted with EtOAc (100 mL). The solid that formed was collected, washed with EtOAc (20 mL), and dried to give 2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (3.5 g, 23.62 mmol, 19.4% yield) as a beige soild. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br. s., 1H), 6.04 (s, 1H), 2.41 (s, 3H), 2.21 (s, 3H). MS(ES) [M+H]+ 148.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[ClH:36]>C(Cl)Cl.CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (74 mg, 0.15 mmol) in CH2Cl2 (3 mL) and methanol (1 mL) was added 2 N HCl (2 mL, 2M in Et2O). The mixture stirred for 4 h at ambient temperature. The reaction mixture was diluted with Et20 (30 mL) and the resulting solids were collected by filtration to give (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride as a white solid (64 mg, 98%): 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.16 (br s, 2H), 7.73-7.68 (m, 1H), 7.59-7.50 (m, 2H), 4.84-4.69 (m, 1H), 4.32-4.25 (m, 2H), 3.26-3.03 (m, 2H), 2.89-2.81 (m, 2H), 2.68-2.48 (m, 4H), 1.73 (m, 4H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCCN(CCC)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methyl-N,N-dipropyl-benzenesulfonamide (Intermediate 148), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [ClH:1].O1CCO[CH2:4][CH2:3]1.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].C(O)C>>[ClH:1].[NH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:3][CH3:4])=[O:14]
Reactant: NCCOCC(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COCCN

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4M, 32.7 ml, 131 mmol) was added to a solution of 2-(2-aminoethoxyl)acetic acid (1.56 g, 13.10 mmol) in ethanol (38.2 ml, 655 mmol) and heated for 2 h at a gentle reflux. The reaction mixture was evaporated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, br, 3H), 4.18 (s, 2H), 4.17-4.08 (m, 2H), 3.75-3.68 (m, 2H), 2.99-2.90 (m, 2H), 1.20 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)CN(C(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(N)cc1
Yield: 100 %

Procedure:
The compound from step b above (3.05 g, 10 mmol) was dissolved in a mixture of methanol (100 mL) and methylene chloride (15 mL) and hydrogenated in the presence of 10% palladium on activated carbon (700 mg) using a hydrogen balloon at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.74 g, ˜100%) which was used direct for the next step. 1H NMR (400 MHz, CDCl3) δ: 7.13 (d, 2H), 7.63 (d, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.65 (brs, 2H).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=1)C1C=CC=CC=1.C(Cl)Cl.Cl>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[C:13]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:14]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)cc1O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a mixture of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone (reference example 14-1) (526 mg) and methylene chloride (22 mL) was added titanium(IV) chloride (0.288 mL) at room temperature. After stirring for 30 minutes, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture at room temperature. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50%-67% ethyl acetate/hexane, gradient elution) to give the title compound (383 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][F:17])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])[CH2:15][CH2:16][F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CCF)c1cnccc1I
Product: CC(C)(C)OC(=O)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (2-fluoro-ethyl)-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1). Yellow oil (86%). MS (ESI): m/z=351.13 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Al](Cl)(C)C.[CH3:12][S:13]([C:16]1[CH:43]=[CH:42][C:19]([O:20][C:21]2[C:26]3[CH:27]=[C:28]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[O:29][C:25]=3[CH:24]=[C:23]([C:37](OCC)=[O:38])[CH:22]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClCCCl>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:37]([C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:42]=[CH:43][C:16]([S:13]([CH3:12])(=[O:14])=[O:15])=[CH:17][CH:18]=3)[C:26]3[CH:27]=[C:28]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[O:29][C:25]=3[CH:24]=2)=[O:38])=[N:3]1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(CN4CCCC4=O)oc3c2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
To a solution of 3-amino-1-methyl pyrazole (106 mg, 1.09 mmol) in DCE (10 mL) at 0° C. was added Al(CH3)2Cl (1.09 mL, 1M in hexanes) drop-wise. After removal of the ice-bath, the mixture was stirred for min at room temperature. Ethyl 4-(4-(methylsulfonyl)phenoxy)-2-((2-oxopyrrolidin-1-yl)methyl)benzofuran-6-carboxylate (50 mg, 0.11 mmol) was added and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (22 mg, 47%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.97-2.13 (m, 2 H) 2.44 (t, J=8.01 Hz, 2 H) 3.08 (s, 3 H) 3.46 (t, J=6.97 Hz, 2 H) 3.81 (s, 3 H) 4.60 (s, 2 H) 6.54 (s, 1 H) 6.79 (d, J=2.26 Hz, 1 H) 7.09-7.17 (m, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.44 (s, 1 H) 7.81-7.98 (m, 3 H) 8.54 (s, 1 H). LCMS m/z 509.0 (M+H)+.