Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29]([C@H:31]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (175 mg, 0.91 mmol) and Et3N (127 μL, 0.91 mmol) in anhydrous DCM (8.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (219 mg, 0.91 mmol) and DMAP (22 mg, 0.18 mmol) and stir the resulting solution for 10 min. Add cis-4-Amino-cyclohexanecarboxylic acid methyl ester (74) (136 mg, 0.87 mmol) and stir the reaction solution 2d at rt Remove solvent and purify the crude product by flash chromatography (silica gel, EtOAc/CyH 3+1, later EtOAc) to obtain cis-{4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid methyl ester (75) (254 mg, 76%) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): 1.40-1.51 (m, 2 H); 1.59-1.70 (m, 4H); 1.70-1.82 (m, 2H); 2.40-2.48 (m, 3H); 2.88 (t, 2H, J=7.6 Hz); 3.65 (s, 3H); 3.79 (s, 3H); 3.82 (s, 6H); 3.86-3.95 (m, 1H); 5.33 (br.d, 1H, J=7.3 Hz); 6.40 (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 87.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and tert-butyl isocyanate (65 μL, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a colourless glass (204 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][C@H:17]1[C:25]([O:27]CC)=[O:26])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][C@H:17]1[C:25]([OH:27])=[O:26])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2CCCCC2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.22 g of 1-[N-benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid, ethyl ester in 150 ml of methanol, add 20 ml of 2.5N sodium hydroxide and stir the mixture at room temperature for 18 hours. Concentrate the mixture under nitrogen, dilute the residue with ice-water and then make the mixture acidic with concentrated hydrochloric acid. Extract the aqueous solution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic phase and place it on a column of silica gel (500 g., 60-200 mesh). Elute with chloroform:glacial acetic acid 9:1 to give 1- [N-benzyloxycarbonyl-(S)-alanyl ]octahydroindole-2(S)-carboxylic acid, a white solid [α]D26 62.1° (ethanol), m.p. 58.60°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[C:31]1([CH2:41][NH2:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:42][CH2:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: NCc1cccc2ccccc12
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (3.0 g, 6.86 mmol) (Preparation 10), 1-naphthalenemethylamine (1.2 g, 7.63 mmol), and triethylamine (2.8 g, 27.72 mmol) in acetonitrile (30 ml) was left to stand at room temperature for 2 hours during which time a fine precipitate slowly formed. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (150 ml) and water (50 ml). The organic phase was separated and the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was azeotroped with dichloromethane to afford the title compound as a foam (3.6 g).
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].P(Cl)(Cl)(Cl)=O>>[Cl:22][C:7]1[C:6]2[CH:1]=[CH:2][C:3]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reaction time: 0.5 h

Procedure:
At room temperature, add 14.25 gm. (50 mmole) of methyl 10,11-dihydrodibenzo[b,f][1,4]-thiazepin-11-one-3-carboxylate to a stirred mixture of 10.425 gm. (50 mmole) of phosphorous pentachloride in 50 ml. of phosphorous oxychloride. Stir for 30 minutes, add an additional 1 gm. of phosphorous pentachloride and continue stirring for one hour. Partition the reaction mixture between a mixture of 400 ml. of methylene chloride, 350 gm. of ice and 150 ml. of water. Separate the aqueous layer and extract with 50 ml. of methylene chloride. Wash the combined organic extracts with a mixture of 100 gm. of ice and 100 ml. of water. Dry the methylene chloride solution over magnesium sulfate, charcoal and filter. Evaporate the solution, take-up in 50 ml. of dry toluene and again evaporate. Take up the residue in 25 ml. of acetonitrile, cool in an ice bath and separate the precipitate by filtration to obtain the title product. (m.p. 134°-135.5° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:12][CH2:13]2)=[O:10])[N:7]=1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1nccc(B(O)O)c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1Cl
Temperature: 80 °C
Yield: 50.6 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 3-chloro-2-methoxypyridin-4-ylboronic acid (73 mg, 0.39 mmol), tetrakis(triphenylphosphine)-palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-20% ethyl acetate in hexanes) to yield the product (72 mg, 50%). ESI-MS m/z calc. 473.10. found 474.3 (M+1)+. Retention time 2.19 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].O=S(Cl)Cl.[CH3:26][NH2:27].[OH-].[Na+]>C(Cl)Cl>[CH3:26][NH:27][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CH2Cl2 (12 mL) was added SOCl2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2Cl2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH2Cl2 (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).
Reaction SMILES: [C:1]([C@@H:3]([NH:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]([CH3:27])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:8])[CH2:4][OH:5])#[N:2].F[B-](F)(F)F.[CH3:33][O+](C)C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[C:1]([C@@H:3]([NH:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]([CH3:27])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:8])[CH2:4][O:5][CH3:33])#[N:2]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CO)cc2ccccc21
Reactant: C[O+](C)C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
N-[(1S,2R)-2-({[(1R)-1-Cyano-2-hydroxyethyl]amino}carbonyl)cyclohexyl]-1-methyl-1H-indole-2-carboxamide from Example 4 (0.20 g, 0.54 mmol) was dissolved in dichloromethane (8 mL), cooled to 0° C. under nitrogen in the dark, and stirred for 15 minutes. Trimethyloxonium tetrafluoroborate (0.10 g, 0.68 mmol) was added (Sowinski, J. A.; Toogood, P. L. J. Org. Chem. 1996, 61, 7671). After 20 minutes, proton sponge (0.14 g, 0.65 mmol) was added, and the reaction was allowed to warm to room temperature and was stirred for 21 hours. The reaction mixture was filtered through a pad of celite and the pad washed with dichloromethane. The filtrate was washed with 1M hydrochloric acid, brine, dried on magnesium sulfate, and concentrated. Purification by column chromatography (5:95 methanol:dichlormethane) gave 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[((R)-cyano-methoxymethyl-methyl)-carbamoyl]-cyclohexyl}-amide (0.08 g, 38%). MS: 383 (M+H).
Reaction SMILES: [O:1]1[CH2:31][CH:2]1[CH2:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][CH2:26][C:27]#[N:28])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH3:32][NH:33][CH3:34].O>CN(C=O)C>[CH3:32][N:33]([CH2:31][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][CH2:26][C:27]#[N:28])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)[CH3:34]
Reactant: N#CCCN(c1cc(Nc2ccc(OCC3CO3)cc2)ncn1)c1cc(Cl)ccc1Cl
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(O)COc1ccc(Nc2cc(N(CCC#N)c3cc(Cl)ccc3Cl)ncn2)cc1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 4-{4-[2,3-epoxypropoxy]anilino}-6-[N-(2-cyanoethyl)-2,5-dichloroanilino]pyrimidine (Reference Example 7, 396 mg) in DMF (2 ml) was added dimethylamine (2M in MeOH, 3.5 ml) and the reaction stirred for 6 hours. The mixture was poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 91:8:1 to give the product (366 mg, 84%) as a colourless oil. NMR: 2.15 (6H, s), 2.20-2.42 (2H, m), 2.84 (2H, m), 3.72-4.22 (5H, m), 4.77 (1H, d), 5.27 (1H, s), 6.81 (2H, d), 7.37 (2H, d), 7.56 (1H, dd), 7.76 (2H, m), 8.22 (1H, s), 8.88 (1H, s); m/z 501 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To 5-trifluoromethyl-2(1H)-pyridone (10.0 g, 61.3 mmol) and sodium acetate (5.25 g, 64 mmol) in acetic acid (100 ml) was added bromine (3.3 ml, 63 mmol) and the solution stirred at 80° C. for 2 hrs. After concentration in vacuo, the residue was suspended in saturated sodium bicarbonate solution (500 ml) and extracted with ethyl acetate (2×50 ml). The extracts were dried (MgSO4) and concentrated to give the product as a tan solid (14.22 g, 58.8 mmol, 96% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[F:29][C:30]1[C:39]([F:40])=[C:38]([CH2:41][CH2:42][OH:43])[CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(O)(=O)C>[F:29][C:30]1[C:39]([F:40])=[C:38]([CH2:41][CH2:42][OH:43])[CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH2:34][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: O=CCOc1ccc(CCO)c(F)c1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CCO)c(F)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.5 g) was added to a solution of 2-(2,3-difluoro-4-(2-hydroxyethyl)phenoxy)acetaldehyde (example 77, step d) (0.31 g) in N-methyl-2-pyrrolidinone (10 mL) and acetic acid (0.07 mL). The resulting mixture was stirred for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.38 g) was then added and the reaction was allowed to warm to RT and stirred overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was basified with saturated sodium hydrogen carbonate solution and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with water (100 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 47.5:47.5:5 isohexane:ethylacetate:triethylamine to 5% triethylamine in ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a clear gum. Yield 0.41 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]#[N:23].Cl>CC(C)=O.O>[C:22]([CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)#[N:23]
Reactant: N#CCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 4-hydroxybenzoate (30.0 g, 0.20 mol), sodium iodide (30.0 g, 0.20 mol) and potassium carbonate (27.6 g, 0.20 mol) in acetone (2000 mL) was added chloroacetonitrile (14.9 g, 0.20 mol). The mixture was stirred at RT for 3 days. Water was added and the mixture was acidified with 1N hydrochloric acid and the mixture was extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in acetone and chloroacetonitrile (6.04 g, 0.08 mol), sodium iodide (12.0 g, 0.08 mol) and potassium carbonate (11.1 g, 0.08 mol) were added and the mixture was stirred for 16 hours at RT and at 60° C. More chloroacetonitrile was added until the conversion was 97%. Water was added and the mixture was acidified with 1N hydrochloric acid and the mixture was extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford methyl 4-cyanomethyloxybenzoate in quantitative yield. This compound was used without further purification in the following step.
Reaction SMILES: [Li+].[BH4-].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:17][CH2:16][S:15][C@H:14]2[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22](OC)=[O:23])[N:13]2[C:12]1=[O:26])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[OH:23][CH2:22][C@H:21]1[N:13]2[C@@H:14]([S:15][CH2:16][CH2:17][C@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[C:12]2=[O:26])[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
LiBH4 (2 M in THF, 1.57 mL, 3.14 mmol) was added dropwise to a 0° C. solution of (4S,7S,10aS)-methyl 4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (750 mg, 2.09 mL) in THF (8 mL). The reaction mixture was then stirred at rt overnight. The reaction mixture was cooled to 0° C. and carefully quenched by slow addition of saturated aqueous NH4Cl. After 10 min of stirring, the mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give tert-butyl (4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (513 mg, 1.55 mmol, 74.2% yield) as a white solid. Anal. Calcd. for C15H26N2O4S m/z 330.4. found: 330.9 (M+H)+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](O)=[N:12][N:11]=[CH:10]2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:14]2[C:9](=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:18])=[CH:16][CH:15]=2)[CH:10]=[N:11][N:12]=1
Reactant: Cc1ccccc1-c1ccc2c(O)nncc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-c1ccc2c(Cl)nncc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 6-o-tolylphthalazin-1-ol (3.65 g, 15 mmol) and phosphorus oxychloride (15 mL, 161 mmol) was stirred at 110° C. for 16 h. After cooling to RT, the phosphorus oxychloride was removed in vacuo. The residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous Na2O3 and brine. The organic solution was dried over magnesium sulfate, and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate: hexane 60:40) gave 1-chloro-6-o-tolylphthalazine as a yellow solid. MS (ESI, pos.ion) m/z: 255.0 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19](I)=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=3[Cl:36])=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(I)c2n1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(-c3cccc(Cl)c3Cl)c2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
A suspension of cyclopentyl-[2-(3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino)-ethyl]-carbamic acid tert-butyl ester (38 mg, 0.076 mmol) and 2,3-dichlorobenzeneboronic acid in toluene (0.5 mL)/ethanol (0.5 mL)/2 M aqueous sodium carbonate (0.22 mL) was degassed (3×) by alternately pulling a vacuum followed by repressurization with nitrogen. Tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol) was added, and the mixture was degassed (3×) again. The mixture was stirred for 2.5 hours at 100° C., concentrated under reduced pressure, and then chromatographed (4:1 hexanes/ethyl acetate) to give the product as colorless oil (24 mg, 60%): +APcI MS (M+1)+ 518; 1H NMR (CDCl3) δ7.42 (dd, 1 H), 7.30 (dd, 1H), 7.22 (t, 1H), 5.84 (s, 1H ), 4.25-4.10 (br s, 1H), 3.49 (s, 4H), 2.44 (s, 3H), 2.32 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].C([N:14]1[CH2:19][CH2:18][CH:17](OC2C=CC(Cl)=CC=2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: Clc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCCC1

Procedure:
12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride.