Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]([CH3:51])[CH2:45][CH2:46][O:47][CH2:48][CH2:49]O>>[ClH:1].[CH3:43][N:44]([CH3:51])[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: CN(C)CCOCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCOCCN(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(2-(dimethylamino)ethoxy)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-dimethylamino-ethoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C37H42Cl2F2N4O5: (M+): 731. found: 731.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][C@@H:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[OH:33]>CO>[CH3:13][N:14]([C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[OH:33])[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: O=Cc1cccc2ccccc12
Reactant: Oc1ccc2ccccc2c1
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CO
Product: C[C@@H](c1ccccc1)N(C)[C@@H](c1cccc2ccccc12)c1c(O)ccc2ccccc12
Temperature: 85 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
1-Naphthaldehyde (2.7 mL, 20 mmol), (S)-(−)-N,α-dimetylbenzylamine (2.60 g, 19 mmol) and 2-naphthol (2.43 g, 16 mmol) are charged into a 25 mL flask with a magnetic stirring bar. The mixture is heated to 85° C. and stirred for 72 h. After the system is cooled to RT, MeOH (5 mL) is added and the precipitated product is collected by filtration, washed with MeOH (5 mL) and dried to afford 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol as white crystals (about 51% yield): 1H NMR (500 MHz, CDCl3) δ 14.01 (br s, 1H), 7.77-7.02 (m, 18H), 6.45 (s, 1H), 4.40 (br s, 1H), 1.95 (s, 3H), 1.65 (br s, 3H); MS (EI) m/z (rel intensity) 418 (M++1), 283, 141, 136; HRMS (EI) Calcd for C30H28NO (M++1): 418.2171, found 418.2135.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:27]=[CH:26][C:11]([CH2:12][NH:13][C:14]2[C:24]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][C:15]=2[Cl:25])=[CH:10][CH:9]=1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>O1CCOCC1>[ClH:25].[Cl:25][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[C:14]=1[NH:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[S:37])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][CH:10]=1
Reactant: CC(C)(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=S)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Product: Cl
Temperature: 25 °C

Procedure:
Combine 6-(4-tert-butylcarbamoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo-[d]azepine (0.3 g, 0.67 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (0.3, g, 0.67 mmol) and anhydrous 1,4-dioxane (10 mL) in a sealed tube and heat at 100° C. for 5 h. Cool the reaction mixture to ambient temperature, evaporate the solvent and purify the residue by SCX
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([Cl:35])=[O:34])=[CH:31][CH:30]=1.Cl>O1CCCC1>[ClH:35].[NH2:8][CH:9]([C:33]([C:32]1[CH:36]=[CH:37][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)=[O:34])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1ccc(OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
5 g (18.6 mmol) of ethyl N-(diphenylmethylene)glycinate in solution in 20 ml of tetrahydrofuran are added to a solution of 18.7 ml (18.6 mmol) of 1N potassium tert-butoxide in 20 ml of tetrahydrofuran cooled to −70° C. After stirring for 30 minutes, this mixture is added to a solution containing 3.2 g (18.6 mmol) of 4-methoxybenzoyl chloride in 20 ml of tetrahydrofuran at −70° C. One hour after the addition, the reaction medium is hydrolysed with a 1N aqueous solution of hydrochloric acid and concentrated. The residue is taken up in water and extracted with diethyl ether. The organic phase is dried over magnesium sulphate and the solvent is then evaporated off. 5.5 g of ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride are obtained with a quantitative yield.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CN1CC[O:16]CC1.O.[F:20][C:21]([F:35])([F:34])[C:22](Cl)=[N:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1>C(OCC)(=O)C>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:16][C:22](=[N:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1)[C:21]([F:35])([F:34])[F:20])(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc(NN=C(Cl)C(F)(F)F)c1
Reactant: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(=NNc2cccc(C#N)c2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(3-cyano)phenyl-2-(trifluoroacetyl)hydrazine (1, 22.9 g, 0.1 mol) in ethyl acetate (180 mL) was treated with p-toluenesulfonyl chloride (24.8 g, 0.13 mol, 1.3 equiv) at 0° C. under N2, and the resulting reaction was added dropwise a solution of N-methylmorpholine (NMM, 11.11 g, 12.1 mL, 0.11 mmol, 1.1 equiv) at 0° C. under N2. The reaction mixture was then stirred at 0° C. for 10 min before being gradually warmed to room temperature for 3-4 h. When the HPLC showed that the reaction had a greater than 95% conversion, the reaction mixture was treated with water (200 mL) and EtOAc (300 mL). The resulting mixture was stirred at room temperature for 30 min. The two layers were then separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with water (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residual ethyl acetate solution (100 mL) was added heptanes (400 mL), and the resulting mixture was stirred at room temperature for 1 h to precipitate the desired tosylate. The solids were collected by filtration, washed with EtOAc-hexanes (1:5, 2×50 mL) and dried in vacuo. The crude desired 2,2,2-trifluoro-N-(3-cyanophenyl)ethanehydrazonoyl tosylate (5, 31.03 g, 38.3 g theoretical, 81%) was obtained as pale-yellow solids, which was found to be >96% pure by HPLC. The only observable impurity (3-4%) was found to be the corresponding iminoyl chloride (2), which will not affect the following cycloaddition reaction. The analytically pure product (5) was obtained from flash column chromatography (SiO2, 5-20% EtOAc-hexanes gradient elution) purification or recrystalization (EtOAc/heptanes) of the crude 5 obtained above. For 5: CIMS m/z 382 (M+−H, C16H12F3N3O3S).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=CN(C)C)[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CO[CH:25](OC)[N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)Cl.CO.CO>O>[C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=[CH:25][N:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:31][CH:32]([CH3:33])[CH3:34])[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: COC(OC)N(CC(C)C)CC(C)C
Reactant: CN(C)C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)CN(C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)CC(C)C

Procedure:
As described for 9a but using N,N-di-isobutylformamide dimethylacetal. Colorless crystals (72%). M.p. 138-140°C. TLC (silica gel, CH2Cl2-MeOH, 9:1): Rf 0.40. UV (10% MeOH in water): λmax 236 (10100), 325 nm (25850). 1H-NMR ([D6]DMSO): δ 0.88, 0.94 (2d, 12 H, CH3); 1.95, 2.20 (2m, 2H, CH); 2.80 (2m, 2H, H2—C(2′)); 3.30-3.74 (m, 6H, H2—C(5′) and 2 CH2); 4.00 (m, 1H, H—C(4′)); 4.45 (m, 1H, H—C(3′)); 5.03 (t, 1H, 3J(H,H)=4.9 Hz, 5′—OH); 5.37 (d, 1H, 3J(H,H)=4.0 Hz, 3′—OH); 6.54 (t, 1H, 3J(H,H)=6.4 Hz, H—C(1′)); 8.78 (s, 1H, N═CH); 9.10 (s, 1H, H—C(8)). Anal. calcd. for C18H29N7O3. 1/2 H2O (400.5): C, 53.99; H 7.55; N 24.48; found: C 53.65; H 7.62; N 24.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h
Yield: 109.3 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-nitroindole (0.550 g, 1.39 mmol) in a mixture of ethanol (120 mL) and THF (40 mL) was added 10% palladium-on-charcoal (0.30 g) and the mixture was hydrogenated in a Parr shaker at 40 psi for 18 h. The mixture was then filtered through Celite and the cake was washed with additional ethanol-THF. Evaporation of the filtrate gave the essentially pure title compound (0.557 g, 100 %) as a brown foam. A sample of this material (0.143 g ) was treated with excess methanolic HCl and the resulting solution was diluted with acetone to give a precipitate. The precipitate was filtered and then it was crystallized from ethanol to give 0.100 g of a purplish solid, m.p. 192° C. (dec). IR (KBr) 3410, 3200, 1630, 1540 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.22 (br s, 1H), 10.20 (br s, 2H), 8.60 (d, 1H), 8.20 (s, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.6, 1.9 Hz, 1H), 4.89-4.82 (m, 2H), 3.91 (s, 3H), 3.8-3.0 (br m, 8H), 2.76 (m, 2H), 2.12 (br m, 2H). Anal. Calcd. for C20H26N6O.4HCl.H2O: C., 45.29; H, 6.08; N, 15.85. Found: C., 45.32; H, 5.97; N, 15.59.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[CH3:39])=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:38][C:34]1[C:33]([CH3:39])=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][C:17]1[C:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[C:24]2[N:19]([C:18]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:20]=[CH:21][CH:22]=[CH:23]2
Reactant: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccn2c1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCNCC2)c2ccccn2c1-c1ccccc1
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of the compound of step 5 (158 mg, 299 mmol) in DCM (8 ml) and TFA (4 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the residue was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 108 mg of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
Reaction SMILES: [NH3:1].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13](Cl)(=[O:15])=[O:14])(=[O:5])=[O:4]>O1CCCC1>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:1])(=[O:15])=[O:14])(=[O:5])=[O:4]
Reactant: N
Reactant: CS(=O)(=O)Oc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccccc1S(N)(=O)=O

Procedure:
Ammonia was passed at -30° C. into a solution of 130.3 g of 2-chlorosulfonylphenyl methanesulfonate in 1 l of tetrahydrofuran, and the conversion was checked by thin-layer chromatography. After the reaction was complete, the tetrahydrofuran was distilled off under reduced pressure from a water pump and the residue was triturated with water and diethyl ether. This gave 110.2 g (91%) of the title compound of melting point 131°-132° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:47])[F:48])[CH:36]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 11 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-trifluoromethyl-phenyl)piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (8.2 mg, 11%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=O)([CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].O1CCNC1>[Ni].CO>[NH2:10][C:2]([CH3:3])([CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1]
Reactant: CCCCC(O)C(C)(C)[N+](=O)[O-]
Agent: [Ni]
Agent: C1COCN1
Solvent: CO
Product: CCCCC(O)C(C)(C)N
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Catalytic hydrogenation of the 2-methyl-2-nitro-3-heptanol to the 2-amino-2-methyl-3-heptanol. A sample of 2-amino-2-methyl-3-heptanol (2A2M3H) was synthesized by the reduction of the 2-methyl-2-nitro-3-heptanol by a Parr Autoclave unit. The stainless steel, 2 liter autoclave was loaded with Grace 3201 Raney Nickel (RaNi, 90 g wet, 45 g dry, 10 wt %) and methanol (MeOH, 300 g). The autoclave was sealed, assembled, purged with nitrogen then hydrogen, pressurized with hydrogen, stirred at 600 RPM, and warmed to 40° C. The yellow nitro-alcohol (422 g) had been diluted with absolute ethanol (EtOH, 150 g) and was pumped into the autoclave (4 ml/min) After 3 h the addition was complete and after 3.5 h the reaction was judged complete as no hydrogen uptake was observed. The autoclave was cooled, stirring stopped, vented, and purged with nitrogen. The autoclave was disassembled and the contents were vacuum filtered to remove the RaNi catalyst. This resulted in the isolation of a light yellow liquid (80 area %) that was concentrated in vacuo (55° C./full vacuum) before product was taken overhead (50-52° C./full vacuum). This resulted in the isolation of a clear, colorless, solid (268 g, 91.9 area %, 57% overall yield) that contained some oxazolidine (4.9 area %).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CC(C)NC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and isopropylamine. MS (ESI): 400.3 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:9][N:10]=1)(=[O:4])[CH2:2][CH3:3].[Cl-].[NH4+].O.O1CCCC1>C(O)C.[Fe]>[C:1]([NH:5][C:6]1[S:7][C:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:9][N:10]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Yield: 96 %

Procedure:
To a mixture of 2-propionylamino-5-(4-nitrophenylthio)thiazole (3 g), and ammonium chloride (1 g) in a mixture of ethanol (100 ml), water (30 ml) and tetrahydrofuran (70 ml) was portionwise added the iron powder at 80° C. with stirring. The mixture was refluxed for 2hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was triturated with water, the precipitates were collected by filtration and washed with water to give solid. The solid was recrystallized from ethanol to give 2-propionylamino-5-(4-aminophenylthio)thiazole (2.6 g, yield: 96.3%).
Reaction SMILES: [CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][I:19]>CO>[IH:19].[CH3:18][NH+:6]1[C:7]2[C:15]([N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:16][C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: CI
Reactant: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Solvent: CO
Product: C[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Product: I
Temperature: 120 °C
Yield: 50 %

Procedure:
A mixture of quindoline (2.0 g, 9.2 mmol) from Example 2, methanol (5 mL) and methyl iodide (880 mL, 14.1 mmol) was heated in a bomb at 120° C. for 4 hours. After cooling, the resulting brown precipitate (2.5 g, 75.5%) was filtered and washed with ether. Recrystallization from water gave the title compound as bright yellow crystals, yield 50%, mp 283.5°-284° C. [lit 284°-286° C. (Gellert, E.; Raymond-Hamet; Schlittler, E. Helv. Chim. Acta 1951, 34, 642-651)]; 1H NMR (DMSO-d6) δ 12.87 (s, 1H, NH), 9.28 (s, 1H, H11), 8.79 (d, J=8.4, 1H, H6), 8.75 (d, J=9.2, 1H, H4), 8.57 (d, J=8.3, 1H, H1), 8.16 (t, J=7.6, 1H, H3), 7.94-7.92 (dd, J=7.2, J=7.0, 2H, H2 and H8), 7.82 (d, J=8.4, 1H, H9), 7.51 (t, J=7.0, 1H, H7), 5.02 (s, 3H, NCH3); 13C NMR (DMSO-d6) δ 145.62, 137.97, 135.25, 133.87, 133.16, 132.34, 129.76, 126.99, 126.21, 126.13, 124.72, 121.31, 117.78, 113.76, 113.10, 40.19; MS (EI, m/z) 232.1 (M+) .
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9](Cl)=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]=1[Cl:15]>O>[NH2:3][C:4]1[CH:9]=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]=1[Cl:15]
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(C(=O)O)c1Cl
Reaction time: 0.5 h

Procedure:
To a 4-liter (L) flask was added 2400 grams (g) of hot water, 250 g of 50 percent by weight NaOH, and 350 g of wet 4-amino-3,5,6-trichloropyridine-2-carboxylic acid (80 percent). The solution was stirred for 30 minutes (min), filtered through a 1 micron polypropylene film, and transferred to a 5-L feed circulation tank. This solution weighed 3000 g and contained 9.3 percent 4-amino-3,5,6-trichloropyridine-2-carboxylic acid and 2.0 to 2.5 percent of excess NaOH.
Reaction SMILES: CN1C(=O)CCC1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].C(=O)(O)[O-].[Na+]>CC#N.O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH:27][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:35]([CH3:42])[CH3:34])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: CN(C)CC=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C

Procedure:
A 3 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged N-methyl pyrrolidinone (0.77 kg, 0.75 L, d=1.033 g/mL). At ambient temperature is added 4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline (0.0748 kg). The reaction mixture is heated to 40–45° C. and maintained for about (15 minutes). The reaction mixture is cooled to (0–10° C.) and the light suspension of 4-(dimethylamino)-2-butenoyl chloride hydrochloride in CH3CN added via dip tube and positive nitrogen pressure, over (30–45 minutes) while maintaining the temperature (0–10° C.) for at least (2 hours). Reaction completion is monitored by HPLC. The reaction is complete when there is ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline) present. To a 12 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged with water (2.61 kg, 2.61 L) and sodium bicarbonate (0.209 kg) with stirring until a solution is obtained followed by cooling to (20–24° C.) to which is transferred the reaction mixture above which contains ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline), via dip tube and positive nitrogen pressure, to the 12 L flask over about (45–60 minutes) while maintaining the temperature at (20–24° C.). The temperature is maintained at (20–24° C.) for at least (1 hour). Filter the reaction mixture on a Buchner funnel, rinse with water (3×0.40 kg, 3×0.40 L), and maintain suction until dripping stops. Dry the product in a vacuum oven at about (50° C.) and about (10 mm Hg) for about (28–30 hours). The yield is 78.5 g (86%) at 79.7% strength and 12.3% total impurities.