Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[N:6][N:5]([CH2:13][C:14](=O)[CH3:15])[CH:4]=2.[Si]([O:24][CH:25]([CH3:39])[CH2:26][N:27]1[CH:35]=[C:34]2[C:29]([C:30]([Cl:38])=[C:31]([Cl:37])[CH:32]=[C:33]2[Cl:36])=[N:28]1)(C(C)(C)C)(C)C.[N+:40](C1C(Cl)=C(Cl)C=C(Cl)C=1C=O)([O-])=O>>[NH2:40][C:14]([CH3:15])([CH2:13][N:5]1[CH:4]=[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:2]2[Cl:1])=[N:6]1)[C:26]#[N:27].[Cl:36][C:33]1[C:34]2[C:29]([C:30]([Cl:38])=[C:31]([Cl:37])[CH:32]=1)=[N:28][N:27]([CH2:26][C:25](=[O:24])[CH3:39])[CH:35]=2
Reactant: O=Cc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Product: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Yield: 58.5 %

Procedure:
2-Amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.16 g, 60%) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(4,6,7-trichloro-2H-indazol-2-yl)propan-2-one (0.25 g). 1-(4,6,7-Trichloro-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part c and d except starting from 2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6,7-trichloro-2H-indazole (1.4 g, 69%) that was prepared using a procedure similar to that described in Example 132 part a except starting from [2-(tert-butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzypamine (2.2 g). [2-(tert-Butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzypamine (2.2 g, 44%) was prepared using a procedure similar to that described in Example 105 part a except starting from 2-nitro-3,4,6-trichlorobenzaldehyde (3 g) that was prepared as follows:
Reaction SMILES: C(=O)([O-])[O:2][CH:3]([CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15])[C:4]([Cl:7])([Cl:6])[Cl:5].[Na+].[P:20](Cl)([Cl:22])[Cl:21]>>[P:20]([Cl:22])([Cl:21])[O:2][CH:3]([CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15])[C:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: ClP(Cl)Cl
Reactant: COC(=O)C1C(C(OC(=O)[O-])C(Cl)(Cl)Cl)C1(C)C
Agent: [Na+]
Product: COC(=O)C1C(C(OP(Cl)Cl)C(Cl)(Cl)Cl)C1(C)C
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
A 10-ml flask was charged with sodium 2,2,2-trichloro-1-(2,2-dimethyl-3-methoxycarbonylcyclopropyl)ethyl carbonate (compound 4, 0.73 mmol) and phosphorus trichloride (0.80 mmol) and stirred at 40° C. for 45 min. Then, the excess of phosphorus trichloride was removed at sub-atmospheric pressure. The conversion of compound 4 was at least 92%, with a selectivity to the title compound of at least 79%.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[C:14]([CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.I[CH2:38][CH2:39][OH:40]>>[O:1]=[C:2]1[NH:8][C:7]2[C:9]3[C:14]([CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:38][CH2:39][OH:40])[S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: OCCI
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(N(CCO)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1

Procedure:
By using N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide obtained in Example 145, and 2-iodoethanol, the title compound was obtained in the same manner as that of Example 152.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc3c(ccn3Cc3ccc(C(C)(C)C)cc3)c2)c1
Temperature: 70 °C
Yield: 72.9 %

Procedure:
The mixture of 5-bromo-1-(4-tert-butylbenzyl)-1H-indole (67.5 g, 197.2 mmol), 3-methylbenzeneboronic acid (27.6 g, 197.2 mmol), potassium carbonate (27.2 g, 493 mmol), palladium(II) acetate (0.338 g) and tetrabutylammonium bromide (63.5 g, 197.2 mmol) in 10% dioxane in water (degassed, 1.72 L) was stirred at 70° C. The reaction was monitored by TLC. 3-Methylbenzeneboronic acid (45.2 g, 394.4 mmol) was added in four portions every 10 hours, after which time 5-bromo-1-(4-tert-butylbenzyl)-1H-indole was no longer detected by TLC. The reaction was cooled to room temperature and the solvent was decanted. The dark gum-like oil was washed with water and extracted with petroleum ether (4×2 L). The combined petroleum ether extracts were washed with water and filtered. This filtrate was concentrated to a volume of about 1.5 L and allowed to crystallize. The solid was isolated by filtration and dried under vacuum at 60° C. for 10 hours to afford the title compound as a white solid (50.8 g, 73%), mp: 94–95° C. Mass spectrum (ESI, [M+H]+) m/z 354. 1HNMR (400 MHz, DMSO-d6): δ 7.79 (s, 1H), 7.53–7.51 (m, 2H), 7.45 (s, 1H), 7.41 (d, 1H, J=7.79 Hz), 7.37 (d, 2H, J=8.55 Hz), 7.32–7.28 (m, 3H), 7.14 (d, 2H, J=8.40 Hz), 7.09 (d, 1H, J=8.40 Hz), 6.51 (d, 1H, J=2.75 Hz), 5.38 (s, 2H), 2.36 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:2]=1.Cl.Cl.[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH2:35])[CH2:31][N:32]([CH3:34])[CH3:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH:35][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:31][N:32]([CH3:33])[CH3:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCc1cccnc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCc1cccnc1

Procedure:
The title compound, m/e=362.3 ([M−H]−), was produced in analogy with example 1, steps 3 and 4. Thus, 3-pyridinenonanoic acid (U.S. Pat. No. 4,632,925) was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(9-pyridin-3-yl-nonanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)=[O:31]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:17][C:18]([O:20][CH2:29][C:30](=[O:31])[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=2)=[O:19])[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)CCOC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CC1(NC(=O)OCc2ccccc2)CCOC1)OCC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Yield: 118 %

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}tetrahydrofuran-3-yl)acetic acid (Preparation 24, 0.311 g, 1.11 mmol) and triethylamine (0.233 mL, 1.67 mmol) were stirred in acetone (4 mL). A solution of 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (0.315 g, 1.11 mmol) in acetone (4 mL) was added and the reaction heated to 50° C. for 1 hour. Rapid formation of a white precipitate was observed. The reaction was partitioned between dichloromethane and water. The organic layer was separated by phase separation cartridge and concentrated in vacuo to afford the title compound as an oil which was used without purification in the next step (0.634 g, 118% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([Cl:18])=[O:16])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl

Procedure:
A mixture of 4-chloro-α-methoxy-5-nitro-o-toluic acid (3.6 g.) and phosphorus pentachloride (3.0 g.) in 120 ml of benzene is refluxed for thirty minutes. The mixture is then concentrated in vacuo and the residue boiled with 200 ml of hexane and filtered hot. The filtrate is partially concentrated and chilled to give 2.5 g. of white solid with mp 63°-65°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:9]=[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][C:6]3=[N:8][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(N)c(N)n1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Product: CC1CCc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2N1

Procedure:
The title compound was prepared from 6-methylpyridine-2,3-diamine and 1,2-bis(4-fluorophenyl)ethane-1,2-dione analogously to Intermediate E;
Reaction SMILES: C[O:2][CH:3](OC)[C@@H:4]1[O:19][CH2:18][C@H:7]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:5]1[OH:6].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][C@H:7]2[CH2:18][O:19][C@@H:4]([CH:3]=[O:2])[C@@H:5]2[OH:6])=[CH:11][CH:12]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C(OC)OC)[C@@H]2O)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 0° C. solution of 0.340 g of product from Example 321 in 4 ml of methylene chloride is added a solution of 1 ml of trifluoroacetic acid and 0.266 ml of water. The reaction is stirred at room temperature for 1 hour, concentrated in vacuo, extracted with methylene chloride, neutralized with 1 g of sodium bicarbonate, filtered and concentrated in vacuo to give after chromatography (Silica gel: 50-60% ethyl acetate/hexane) 0.222 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[C:28]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-acetyl phenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 279; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1374.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH3:3].Br[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][Si:4]([CH:16]([CH3:18])[CH3:17])([CH:2]([CH3:1])[CH3:3])[CH:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)=[CH:21][C:22]=1[C:29]([F:30])([F:31])[F:32])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)[Si](Oc1ccc(N)cc1)(C(C)C)C(C)C
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a solution of 4-[[tris(propan-2-yl)silyl]oxy]aniline (15 g, 56 mmol) in toluene (100 ml) was added 4-bromo-1-nitro-2-(trifluoromethyl)benzene (22.84 g, 84.6 mmol, 1.5 eq.), Pd2(dba)3 (2.34 g, 2.3 mmol, 4 mol %), BINAP (710 mg, 1.1 mmol, 2 mol %) and t-BuONa (10.87 g, 113.2 mmol, 2 eq.). The mixture was stirred under nitrogen overnight at 100° C. (oil bath). The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether to afford 4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)aniline as a orange solid (8 g, 31%); (ES, m/z): [M+H]+ 455; 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J=6.0 Hz, 1H), 7.05-7.09 (m, 3H), 6.87-6.96 (m, 3H), 6.18 (s, 1H), 1.26-1.33 (m, 3H), 1.13 (s, 18H).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (2.00 g, 0.00522 mol) in 30 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filtered off the catalyst, the filtration was concentrated to dry and used directly in next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)C#N)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-:23].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of 2.0 g of 3-chloro-2-[1-(4-chlorophenyl)-1-cyanomethyl]-5-trifluoromethylpyridine (prepared by the method of Example 1) in 20 ml of dimethyl sulfoxide was admixed with a solution of 2.0 g of potassium carbonate in 3 ml of water, and the mixture was then stirred at 23° C. for 3 days under air. For work-up, the reaction mixture was poured into 200 ml of water. The product of value was then extracted with tert-butyl methyl ether (three times 80 ml). The combined organic phases were washed with water (two times 50 ml each), dried over sodium sulfate and finally concentrated. The resulting black oil was purified by Kugelrohr distillation under reduced pressure. Yield: 1.2 g (62%) of a light-yellow oil; boiling range: 110-120° C. (0.3 mbar); 1H NMR see Ex. 7.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][CH2:10][CH2:11][SH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=[O:17]>CN(C=O)C>[C:3]1([CH2:9][CH2:10][CH2:11][S:12][C:14]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=2[CH:16]=[O:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: SCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1SCCCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a reaction mixture of DMF (40 mL), potassium hydroxide (1.45 g, 25.9 mmol), and 3-phenylpropyl mercaptan (3.28 g, 21.6 mmol), was added 2-chloro-5-nitrobenzaldehyde (4.00 g, 21.6 mmol). The resulting mixture was heated at 100° C. for 45 minutes. The mixture was cooled, poured onto ice-water (350 mL) and allowed to stand at room temperature for 48 hours. A yellow semi-solid which formed was collected and dissolved in ethyl acetate (100 mL), dried over Na2SO4, and filtered. The solvent removed by evaporation to give a dark yellow gum, 6.71 g.1H NMR (CDCl3): d, 10.27 (s,1H,CHO). MS (DCl): 302 (MH+). The crude product was carried on without further purification in example 34. C16H15NO3S.
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19]>CO>[C:17]([OH:26])(=[O:25])[CH:18]([CH:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COC(=O)C1CCN1[C@@H](C)c1ccccc1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate (0.27 g, the ratio: 2S isomer/2R isomer=52/48) and L-tartaric acid (0.15 g) were dissolved in methanol (6 ml) at room temperature. Then, the mixture was concentrated to give tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate, which was recrystallized from a mixed solvent of methyl tert-butyl ether (6 ml) and methanol (2 ml) to give crystals of tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (0.12 g, colorless crystals, yield: 28%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@H:29]1[CH2:33][C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:31]([CH3:42])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:33][C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C@@H:31]([CH3:42])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: C[C@H]1C[C@@H](N)C[C@@H]1NC(=O)OC(C)(C)C
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1S*,2S*,4R*)-4-amino-2-methylcyclopentyl]carbamate (example C33) the title compound is obtained as pale yellow foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19].[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[N:8]([CH3:18])[C:7]3=[O:19])[CH2:23][CH2:22]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C2(CCCCN3CCC(O)(c4ccccc4)CC3)CCCc3cccc1c32
Yield: 54 %

Procedure:
A mixture of 2a-(4-bromobutyl)-1-methyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (322 mg, 1 mmol), 4-hydroxy-4-phenylpiperidine (210 mg, 1.2 mmol), sodium bicarbonate (102 mg, 1.2 mmol) and ethanol (15 ml) was heated under reflux for 6.3 hours on an oil bath, the reaction solution was cooled, and the thus precipitated crystals were collected by filtration to obtain 226 mg of the title compound (0.54 mmol, 54% in yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@H:37]([CH2:39][OH:40])[CH3:38]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:36][C@@H:37]([CH3:38])[CH2:39][OH:40])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)Nc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Yield: 45.4 %

Procedure:
Using the procedure in Example 57, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and L-alaninol (48.4 μL, 0.622 mmol, 2.00 eq) were combined to afford (S)-1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (72 mg, 46% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d4): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.39 (dd, J=2.4 and 8.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.35-7.25 (m, 2H), 6.06 (s, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.09 (brs, 1H), 3.58-3.49 (m, 4H), 3.35 (brs, 1H), 1.23 (s, 9H), 1.17-1.15 (m, 3H); MS (ESI) m/z: 510.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:20](OC)=O.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>CCOCC>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[CH3:20][NH:19][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COC=O
Reactant: COCCCCC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Product: CNC(CCCCOC)C1(c2ccc(Cl)cc2)CCC1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-5-methoxypentylamine [1.7 g prepared in a similar manner to that described in method D hereinbefore (X=Cl, R=3, S=1, T=0.67)] and methyl formate (20 ml) was allowed to stand at ambient temperature for 7 days. The mixture was then filtered to remove a colourless solid which was discarded. The filtrate was evaporated and the residue was dissolved in dry toluene (29 ml). The solution was added dropwise to a 70% solution of bis-(2-methoxyethoxy)aluminium hydride in toluene sold under the trade name Red-Al (4.3 ml) in dry toluene (11 ml) under nitrogen and then the reaction mixture was heated at 50° C. with stirring for 3 hours. The reaction mixture was cooled, and water (20 ml) and 5N sodium hydroxide (15 ml) were added. The aqueous layer was separated and extracted with ether and the extracts combined with the toluene solution, washed with water, dried, filtered and evaporated to give an oil which was dissolved in ether. A solution of maleic acid (0.33 g) in ether was added to give a solid which was recrystallised from propan-2-ol to give N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-5-methoxypentylamine maleate (m.p. 94°-95° C.).