Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]([CH3:29])[CH3:28])[N:19]=3)=[O:17])[CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl>CO>[OH:1][C:2]1([CH2:8][C@H:9]2[NH:10][CH2:11][C@@H:12]([NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]([CH3:29])[CH3:28])[N:19]=3)=[O:17])[CH2:13][CH2:14]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC(C)n1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CC3(O)CCOCC3)NC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 106.6 %

Procedure:
The mixture of tert-butyl cis-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-5-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}piperidine-1-carboxylate (292 mg, 0.583 mmol, step 6 of Example 2) and 10% hydrochloric acid in methanol (3 mL) was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane/methanol (10/1, 10 mL). The solution was filtered through amine-silica gel washing with dichloromethane/methanol (10/1, 200 mL). The filtrate was concentrated under reduced pressure and the resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (10:1:0.2) to give 249 mg (99%) of the title compound as a white crystal.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH:43][C:44]([O:46][C@@H:47]3[C@H:54]4[C@H:50]([O:51][CH2:52][CH2:53]4)[O:49][CH2:48]3)=[O:45])[C@H:23]([OH:42])[CH2:24][N:25]([S:30]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)(=[O:32])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1.CS(C)=O>O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([S:30]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][C@@H:23]([OH:42])[C@@H:22]([NH:43][C:44](=[O:45])[O:46][C@@H:47]3[C@H:54]4[C@H:50]([O:51][CH2:52][CH2:53]4)[O:49][CH2:48]3)[CH2:21][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:57]4[CH2:58][CH2:59][S:55][CH2:56]4)=[CH:20][CH:19]=3)(=[O:32])=[O:31])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: C1CSCN1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCN2CCSC2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 70 °C
Yield: 58.9 %

Procedure:
A mixture of 2-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)ethyl 4-methylbenzenesulfonate (50 mg, 0.06 mmol), thiazolidine (0.02 mL, 0.02 g, 0.25 mmol) and dimethylsulfoxide (1 mL) was heated to 70° C. under nitrogen atmosphere for 2 h. The mixture was diluted with water and extracted with ethyl ether (2×). The organic phase was dried (sodium sulfate), evaporated, and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound (25 mg) as a solid foam. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.6-2.8 (7H, m), 2.8-3.0 (5H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4-0 (2H, br s), 4.05 (2H, br s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.8 (2H, d), 7.0-7.1 (3H, d), 7.18 (1H, d), 7.2 (1H, s), 7.3 (1H, d); MS: 708 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[C:14]([C@@H:18]1[CH2:23][CH2:22][C@H:21](O)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1(C)C=CC=CC=1>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Reaction time: 15 h

Procedure:
To a vial charged with 6-hydroxy-2-naphthonitrile (3.38 g, 0.02 mol, 1.0 eq.), cis-4-tert-butylcyclohexanol (6.24 g, 0.04 mol, 2.0 eq.), PPh3 (10.5 g, 0.04 mol, 2.0 eq.) and toluene (20 mL), was added DIAD (12 mL, 0.06 mol, 3.0 eq.) under nitrogen atmosphere at r.t. and stirred for 15 h. Water was added and extracted with EtOAc. The organic layer was purified by silica gel chromatography (PE:EA=10:1) to give the title compound (9.0 g, 86%) as a slight yellow solid. EDI-MS (M+1)+: 308.0. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:31][OH:32])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]>CCCCCC.CCOC(C)=O>[CH:1]([C:4]1[C:5]([CH:31]=[O:32])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(C(C)C)cc(C(C)C)c(C=O)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 88 %

Procedure:
Prepared from the intermediate obtained in Step A by the procedure described in Example 218, Step A. Silica gel chromatography (95:5 hexane/EtOAc) provided a colorless crystalline solid (0.323 g, 88%). 1H NMR (CDCl3, 300 MHz): δ 9.74 (s, 1H), 7.41 (s, 1H), 7.22-7.28 (m, 3H), 7.06-7.13 (m, 3H), 6.72-6.80 (m, 2H), 5.00 (s, 2H), 3.91 (sept, 6.8 Hz, 1H), 3.23 (sept, 6.7 Hz, 1H), 2.37-2.46 (m, 1H), 2.17-2.27 (m, 1H), 1.20-1.36 (m, 14H), 0.73 (t, 7.4 Hz, 3H). FAB-MS: calculated for C29H33FO2 432; found 433 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b] pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.38 (1H, d, J=5.5 Hz), 7.84-7.74 (2H, m), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.6 Hz), 6.60 (1H, d, J=5.5 Hz), 4.45-4.42 (1H, m), 3.93-3.91 (2H, m), 3.71-3.60 (8H, m), 3.45 (2H, m), 2.56 (3H, s), 2.02-1.98 (2H, m), 1.72-1.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 509, found 509.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH:11]1[C:16](=[O:17])[CH2:15][NH:14][CH2:13][C:12]1=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:40]([C:42]1[C:58]([F:59])=[CH:57][C:45]([O:46][C:47]2[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][C:48]=2[F:56])=[C:44]([O:60][CH3:61])[CH:43]=1)[CH3:41].[Cl-].[NH4+]>ClCCl>[CH2:40]([C:42]1[C:58]([F:59])=[CH:57][C:45]([O:46][C:47]2[CH:55]=[CH:54][C:50]([C:51]([N:14]3[CH2:15][C:16](=[O:17])[NH:11][C:12](=[O:18])[CH2:13]3)=[O:52])=[CH:49][C:48]=2[F:56])=[C:44]([O:60][CH3:61])[CH:43]=1)[CH3:41]
Reactant: O=C1CNCC(=O)N1
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CC(=O)NC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Yield: 94.3 %

Procedure:
The method described in Part E of Examples 431-436 was used to treat 7-bromo-4-chloro-3-nitroquinoline (12.43 g, 43.45 mmol) with C-(tetrahydropyran-4-yl)methylamine (10 g, 87 mmol) to provide 15.0 g of (7-bromo-3-nitroquinolin-4-yl)(tetrahydropyran-4-ylmethyl)amine as a bright yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.42 h
Yield: 57.9 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (248 mg, 0.66 mmole), 2-(tributylstannyl)furan (414 μl, 1.31 mmole) and bis(triphenylphosphine)-palladium(II) dichloride (46 mg, 0.06 mmole) in dimethylformamide (2.5 ml) was stirred at 130° C. for 25 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (140 mg). MS: (+) m/z 367.00 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([O:29]CC)=[O:28])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([OH:29])=[O:28])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(OCc3ccccc3)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 43A in analogy to the synthesis of the compound of Example 71A. 60.0 g (85% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.C[O-].[Na+]>>[OH:4][CH2:3][CH2:2][N:1]1[CH2:5][CH2:6][O:7][C:8]1=[O:9]
Reactant: OCCNCCO
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Product: O=C1OCCN1CCO
Temperature: 135 °C

Procedure:
A mixture of diethanolamine (12.55 g), diethyl carbonate (16.2 mL), and sodium methoxide (80 mg) was heated to 130-140° C. for 1.5 h and distilled during the reaction using a Dean-Stark trap. The remaining liquid was concentrated in vacuo to give 15.11 g (97%) as a yellow oil.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:8]([CH:12]([CH3:14])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.N([O-])=[O:24].[Na+]>S(=O)(=O)(O)O.O.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([OH:24])=[CH:3][CH:4]=3)[N:9]=[C:8]2[CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: O=N[O-]
Reactant: CC(C)c1nc2cc(N)ccc2c(=O)n1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a suspension of the compound of Example 1 (778 mg, 2.479 mmol) in concentrated sulphuric acid/water 972 μL/1.4 mL, cooled to ice bath temperature, is added a solution of sodium nitrite (188 mg) in water (680 μL). The mixture is stirred for 45 minutes at 0-5° C. (internal temperature) and then added to sulphuric acid/water 3/2 (5 mL), pre-heated to 150° C. After stirring for 15 minutes, the mixture is allowed to cool to room temperature, filtered and extracted with EtOAc (3×). The combined EtOAc extracts are washed with water, dried (Na2SO4) and evaporated to a yellow-orange solid. Purification by automated flash chromatography (gradient elution: EtOAc/hexane 0-25%) provides the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH:7]([OH:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>S([O-])([O-])(=O)=O.[Cu+2].CC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[O:16][C:17]([CH3:22])([CH3:18])[O:1][CH:2]2[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(O)C(O)c1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1OC(C)(C)OC1c1ccc(OC)cc1
Reaction time: 16 h

Procedure:
Methyl 2,3-dihydroxy-3-(4-methoxyphenyl)propanoate (3.5 g, 15.5 mmol), copper sulphate anhydrous (4.3 g, 27 mmol, 1.8 equiv.) and acetone (40 ml, excess) were stirred in the presence of a catalytic amount of para-toluene sulphonic acid at 35° C. After 16 hours, the copper sulphate was removed by filtration, and the filtrate was removed and evaporated to dryness on a rotary evaporator. The product was purified by flash column chromatography using DCM as eluant. Evaporation of the appropriate fractions left methyl 5-(4-methoxyphenyl)-2,2-dimethyl -1,3-dioxolane 4-carboxylate as a clear, colourless oil (4.0 g, 96%). [a]D=+37.4° (THF, conc.=0.01712, 20° C). 1H-NMR was in accordance with expected signals.
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:25][CH:26]([NH:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[CH3:25][CH:26]([N:32]([CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[C:7](=[O:9])[CH2:6][S:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCSCC(=O)O
Reactant: CCCCCC(C)NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(C)N(Cc1cccnc1)C(=O)CSCCCC

Procedure:
N-(1-methylhexyl)-N-[(3-pyridyl)methyl]-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 3.6 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide with 5.0 g. of N-(1-methylhexyl)-[(3-pyridyl)methyl]amine in 200 ml. of dichloromethane. Oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[CH3:23])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cc(Br)ccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 16C (2.0 g, 5.15 mmol) in CH2Cl2 (20 ml) was added TiCl4 (6.18 ml, 6.18 mmol) at 0° C. to form a yellow solution. DIEA (1.080 ml, 6.18 mmol) was added at 0° C. to form a blue solution. The mixture was stirred at 0° C. for 1 h. Benzyl chloromethyl ether (1.428 ml, 10.30 mmol) was added and stirring was continued for 2 h at 0° C. at which point the blue turn to brownish red solution. The reaction was quenched with water, diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with sat. NaHCO3 and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate/hexanes). The fractions containing the product was combined, concentrated to give 16D (2.4 g, 4.72 mmol, 92% yield) as a semi solid. 1H NMR (400 MHz, chloroform-d) δ ppm 2.41 (d, J=6.05 Hz, 3H) 2.78-2.93 (m, 1H) 3.30 (d, J=13.19 Hz, 1H) 3.43-3.57 (m, 1H) 4.01-4.23 (m, 3H) 4.46-4.81 (m, 3H) 5.36-5.53 (m, 1H) 7.01-7.16 (m, 1H) 7.18-7.41 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([NH:34][CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([NH:34][CH3:35])=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].I[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[N:11]([CH2:27][CH3:28])[C:10]1=[O:23]
Reactant: CCI
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 90 °C
Yield: 93 %

Procedure:
A solution, cooled in ice, of 100 mg (0.27 ml) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 11 mg (0.27 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of iodoethane and then heated to 90° C. for 2 hours. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 100 mg (92%) of 3-(2,6-dichlorophenyl)-1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]([S-:18])#[N:17].[K+].BrBr.O>CC(O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[C:16]([NH2:17])[S:18][C:14]=2[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#C[S-]
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
4-octylaniline (500 mg, 2.5 mmol), AcOH (4 mL), and KSCN (970 mg, 10 mmol) were stirred at r.t. for 10 min, and then a solution of bromine (0.13 mL, 2.5 mmol) in AcOH (2 mL) was added to the mixture over 20 min. The reaction mixture was stirred at r.t. for 8 h, then poured into cold water and extracted with EtOAc. The organic layer was purified by silica gel chromatography using PE/EA (3/1) to give compound the title compound (460 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.446 (s, 1H), 7.320 (s, 1H), 7.230 (d, 1H), 2.577 (t, 2H), 1.567-1.506 (m, 2H), 1.266-1.167 (m, 10H), 0.847 (t, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[N:9][C:10]=1[Cl:11].CC(C[AlH]CC(C)C)C>CCOCC>[Cl:11][C:10]1[C:5]([CH2:4][CH2:3][OH:2])=[C:6]([Cl:12])[N:7]=[CH:8][N:9]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: OCCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (4,6-Dichloro-pyrimidin-5-yl)-acetic acid methyl ester (0.52 g, 2.35 mmol) in ether (40 mL) at −78° C. was added DIBAL-H (1.5M, 4 mL, 6.05 mmol) dropwise. After addition, the mixture was allowed to warm up to room temperature and stirred for 3 hours. Then quenched with 2N HCl (10 mL) at −78° C. Extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated to give fairly pure 2-(4,6-Dichloro-pyrimidin-5-yl)-ethanol (0.44 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.96 (t, J=6.8 Hz, 2H), 3.23 (t, J=6.8 Hz, 2H). 1.65 (s, 1H). MS (APCI+) [M+H]+194.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].C=O.[C:20](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH3:20])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C)C[C@H]1c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
To a solution of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 31 (500 mg, 2.07 mmol) and formaldehyde (155 μL, 2.07 mmol) in dichloromethane (20 mL) was added acetic acid (188 μL, 2.07 mmol) followed by sodium triacetoxyborohydride (659 mg, 3.11 mmol) at room temperature. The reaction mixture was stirred for 2 hours, diluted with dichloromethane (10 mL) and partitioned with saturated sodium hydrogen carbonate solution (40 mL). The phases were separated and the organic phase was washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colourless oil, 288 mg (54%).