Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Phenyl chloroformate (0.474 mL, 3.77 mmol) was added dropwise to 4-[4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.67 g, 3.77 mmol) and sodium bicarbonate (476 mg, 5.66 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired product (1.90 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[CH2:12](N)[CH2:13][NH2:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]1[NH:14][CH2:13][CH2:12][N:11]=1
Reactant: Cc1ccc(F)c(CC#N)c1
Reactant: NCCN
Product: Cc1ccc(F)c(CC2=NCCN2)c1

Procedure:
2-(2-Fluoro-5-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-fluoro-5-methyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light yellow powder; MS (ISP): 193.0 ((M+H)+.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2cccc(C)c2)c(C(=O)OCC)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNC(=O)Nc1cc(Nc2cccc(C)c2)c(C(=O)O)cn1
Temperature: 75 °C

Procedure:
A suspension of compound vii (0.140 g, 0.410 mmol) in aqueous sodium hydroxide solution (2M, 3 mL) was heated to 75° C. for 48 h, cooled to 0° C. and acidified to pH ˜2 using concentrated hydrochloric acid (35%). The resulting colourless precipitate was filtered, washed with water (3 mL) and air dried to give the desired compound viii. (0.116 g, 0.369 mmol, 90%) as a colourless powder, 1H NMR (300 MHz, DMSO-d6): δ 9.98 (1H, br s), 9.17 (1H, br s), 8.58 (1H, s), 7.94 (1H, br t), 7.30 (1H, t, J 7.7), 7.20 (1H, s), 7.12-7.06 (2H, m), 7.01 (1H, d, J 7.7), 3.13 (2H, dq, J 6.7 and 7.7), 1.05 (3H, t, J 7.2); [M+H]+ m/z=315.1.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:25]([O-])=O)=[CH:4][C:5]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:9][CH2:8][S:7][C:6]=2[CH:24]=1.O.NN>O1CCCC1.CO.C(OCC)(=O)C.[Ni]>[NH2:25][C:3]1[C:2]([F:1])=[CH:24][C:6]2[S:7][CH2:8][CH2:9][N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c([N+](=O)[O-])cc32)CC1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c(N)cc32)CC1
Yield: 97.9 %

Procedure:
To a stirred solution of tert-butyl 4-(7-fluoro-6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)piperidine-1-carboxylate (190 mg, 0.478 mmol) in tetrahydrofuran (3.00 mL) was added Raney-Nickel (28.1 mg, 0.478 mmol) as a suspension in methanol (3 mL). To this mixture was then added hydrazine hydrate (0.233 mL, 4.78 mmol), and the resulting mixture was stirred at 60° C. for 8 minutes. During this time, the reaction mixture turns light red. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (2×), water (2×), and brine. The organic phase was dried, filtered, and concentrated, giving a red oil (172 mg, 98%). 1H NMR (DMSO-d6) δ 6.61 (d, J=11.1 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 4.11-4.01 (m, 2H), 3.62-3.51 (m, 1H), 3.29-3.25 (m, 2H), 2.93-2.88 (m, 2H), 2.87-2.69 (m, 2H), 1.71-1.61 (m, 2H), 1.59-1.48 (m, 2H), 1.40 (m, 9H); ESI-MS (m/z, %): 368 (MH+, 25), 312 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.FC1C=CC(C2CCCN2)=CC=1.BrCC1C=CC(S(Cl)(=O)=O)=CC=1.[CH3:48][O-:49].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:49][CH3:48])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccc(CCl)cc1)N1CCCC1c1ccc(F)cc1
Agent: Fc1ccc(C2CCCN2)cc1
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
Reaction of (RS)-2-(4-fluoro-phenyl)-1-(4-chloromethyl-benzenesulfonyl)-pyrrolidine (0.50 g, 1.41 mmol), which was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromomethyl-benzenesulfonyl chloride, with sodium methanolate in MeOH for 80 h at 50° C. yielded after crystallization from EE/hexane 0.28 g (52%) of the title compound as a white solid, m.p. 115° C., and MS: m/e=349 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]2)[CH:7]=1>[Pd]>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Product: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,2-dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-nitrophenylamino)piperidin-1-yl]ethyl ester (2.3 g, 6.26 mmol) in EtOAC (100 mL) was added a slurry of 10% Pd/C (200 mg) in IMS (20 mL) and the reaction mixture stirred at RT under a hydrogen atmosphere for 24 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 2-6% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum affording the title compound as a dark red oil (1.464 g, 69%). LCMS (Method J): RT 1.71 min [M+H]+ 338.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])[CH2:11][CH2:10]1.[CH3:28][C@@H:29]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[NH:30]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:30]3[C@H:29]([CH3:28])[CH2:33][CH2:32][S:31]3(=[O:35])=[O:34])=[CH:19][C:18]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])[CH2:11][CH2:10]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 57.3 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodo-2-methanesulfonylphenyl)methanone (886 mg) described in Preparation Example 157 and (R)-3-methylisothiazolidine 1,1-dioxide (240 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (514 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[F:31])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccccc1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.29 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:21]([N+:26]([O-])=O)[CH:22]=[N:23]2)=[N:18][CH:17]=1>O.ClCCl.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:21]([NH2:26])[CH:22]=[N:23]2)=[N:18][CH:17]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)CNc1c(N)cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A solution of sodium dithionite (77.95 g, 380.6 mmol) and potassium carbonate (58.35 g, 422.2 mmol) in water (250 mL) was added dropwise to a mechanically stirred solution of 7-bromo-3-nitro[1,5]naphthyridin-4-yl-(2-methylpropyl)amine (27.6 g, 84.6 mmol) and ethyl viologen dibromide (0.63 g, 1.7 mmol) in dichloromethane (300 mL) and water (50 mL). The reaction mixture was stirred overnight at ambient temperature. Water (500 mL) was added, and the reaction mixture was stirred for 10 minutes. The organic layer was separated and the aqueous layer was filtered through WHATMAN paper to remove insoluble material. The emulsion-free filtrate was extracted with dichloromethane, washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 22.3 g of 7-bromo-N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M13) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (50 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7].Cl.[NH2:18][CH2:19][C:20]#[N:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([NH:21][CH2:20][C:19]#[N:18])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: Cc1onc(N[C@@H](CC(C)C)C(=O)O)c1Br
Reactant: N#CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Product: Cc1onc(N[C@@H](CC(C)C)C(=O)NCC#N)c1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To N-(4-bromo-5-methylisoxazol-3-yl)leucine (841 mg, 2.90 mmol), aminoacetonitrile hydrochloride (674 mg, 7.30 mmol), PyBOP (1.73 g, 3.33 mmol) in dry degassed DMF (60 mL) was added triethylamine (1.4 mL, 10.0 mmol) dropwise. The reaction mixture was stirred for 15 hours at room temperature. Aqueous sat. NaHCO3 was added and the product was extracted with diethyl ether (2×) and ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulphate, and concentrated in vacuo. The crude product was purified by flash chromatography (60% ethyl acetate/hexane) to yield N2-(4-bromo-5-methylisoxazol-3-yl)-N1-(cyanomethyl)leucinamide.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: ClCCCBr
Reactant: Oc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1sc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 2-hydroxybenzothiazole (2.0 g, 13.2 mmol) and potassium carbonate (2.74 g, 19.8 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (3.92 mL, 39.7 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 95%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[C:24]([F:26])[CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O>[F:26][C:24]1[CH:25]=[C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][CH:35]=4)[CH2:32][CH2:33]3)[O:27][C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4ncccc4c3O2)cc1
Solvent: CS(C)=O
Product: Fc1cc2c(c3cccnc13)OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2
Temperature: 77.5 °C

Procedure:
0.40 g (1.02 mmole) of (2R)-6-fluoro-2,3-dihydro[1,4]dioxino[2,3-f]-quinolin-2-ylmethyl 4-methylbenzenesulfonate and 0.80 g (4.06 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole were combined in 50 mL of DMSO. The mixture was heated at 75-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to a crude oil under vacuum. This oil was column chromatographed on silica gel using first 1% methanol in methylene chloride to elute impurities and then 5% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum to give 0.085 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 215° C.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.O=C1CCC(=O)N1[C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:43]([O-])=[O:44])=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[CH:32]=2)[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=1>CN(C)C=O.C(OCC)(=O)C>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[C:43]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10])=[O:44])[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=[CH:25]2
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: CN1CCC[C@H](N)C1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
(S)-3-Amino-1-methylpiperidin-2-one hydrochloride (56 mg, 0.34 mmol) was dissolved in triethylamine (95 μL, 0.68 mmol) and N,N-dimethylformamide (1.5 mL). To this solution was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 152 mg, 0.34 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 70% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ie) (94 mg, 60%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 8.61 (br, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.90 (m, 1H), 4.48 (ddd, 1H), 4.22 (d, 2H), 3.36 (m, 2H), 2.97 (s, 3H), 2.73 (m, 1H), 2.36 (m, 1H), 1.99 (m, 2H), 1.66 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C
Yield: 72.3 %

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a pale yellow solution. 2,6-dimethylphenol (385 mg, 3.15 mmol) and potassium carbonate (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated under microwave irradiation (Biotage instrument) at 110° C. for 1 hour. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3 times 10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a pale orange oil (555.9 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:34][CH3:35])=[CH:4][C:5]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)=[C:12]([C:30]([F:33])([F:32])[F:31])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:37]([O-])=O.[Na+]>CN1C(=O)CCC1.O.CCOC(C)=O>[C:8]([C:7]1[C:2]2[N:1]=[N:37][N:34]([CH3:35])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20]3)=[C:12]([C:30]([F:33])([F:31])[F:32])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: CNc1cc(-c2ccc(OCCC3CN(C(=O)OC(C)(C)C)C3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CN(C(=O)OC(C)(C)C)C4)c(C(F)(F)F)c3)cc21
Reaction time: 1 h
Yield: 84 %

Procedure:
tert-Butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl)azetidine-1-carboxylate (100 mg) was dissolved in NMP (1000 μl) and hydrochloric acid (1M, 407 μl) added. A solution of sodium nitrite (20 mg) in water (150 μl) was added at room temperature and the reaction stirred for 1 hour. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (3×20 ml) and brine (20 ml). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to yield crude product as a brown oil. Purification by flash chromatography (DCM to 2% MeOH in DCM mobile phase, 10 g silica column) afforded product tert-butyl 3-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (84% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:40](O)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:40]([O:12][C:11](=[O:13])/[CH:10]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1])\[CH3:14])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OCCc1ccccc1
Reactant: CC(=CC(=O)O)c1ccc(O)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C/C(=C\C(=O)OCCc1ccccc1)c1ccc(O)cc1O
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 9.7 g (0.050 mol) of 3-(2,4-dihydroxyphenyl)but-2-enoic acid in 500 mL of anhydrous tetrahydrofuran (THF) is added 10.3 g (0.050 mol) of 1,3-dicyclohexylcarbodiimide (DCC). After stirring for 10 min, 6.8 g (0.050 mol) of 1-hydroxybenzotriazole (HOBt), 5.5 g (0.045 mol) of phenethyl alcohol and 1.1 g (0.009 mol) of 4-(dimethylamino)pyridine (DMAP) is added and stirred at 0° C. for 1 h, warmed to 22° C. and stirred for an additional 72 h. The mixture is cooled to 0° C., filtered and the solvent is removed under vacuum. The residue is diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, followed by 10% citric acid and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give (E)-3-(2,4-dihydroxyphenyl)-but-2-enoic acid phenethyl ester as a yellow oil that is purified by flash chromatography.
Reaction SMILES: CC(C)[O-].[Dy+3].CC(C)[O-].CC(C)[O-].C(O[SiH](OCC)OCC)C.[C:24](OCC)(=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[OH-].[Na+]>C1COCC1>[CH2:24]([OH:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCC(=O)OCC
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Agent: [Dy+3]
Solvent: C1CCOC1
Product: CCCCCCCCCCO
Temperature: 60 °C
Reaction time: 29 h
Yield: 47.2 %

Procedure:
A dry Schlenk tube under argon was charged with 51 mg (0.15 mmol) of dysprosium (III) isopropoxide. Triethoxysilane (1.4 mL, 7.5 mmol) and ethyl decanoate (696 μL, 3 mmol) were added and the reaction mixture was heated to 60° C. After 29 hours, GLC analysis of an aliquot taken from the reaction mixture showed 23% conversion. The reaction mixture was then heated to 70° C. After an additional 3 days, THF (8 mL) and aqueous NaOH (1 N, 15 mL) were added, and the mixture was stirred vigorously for 3 hours. The reaction was worked up as in Example 13. Purification by flash chromatography (ether:hexane=3:7) afforded 224 mg (47% yield) of decanol (>95% pure by 1H-NMR analysis) and 40 mg of recovered starting material (84% pure, 5.5% yield).