Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].C(N(CC)CC)C.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>Cl.ClCCl>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=Cc1ccnc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A mixture of 2 g of L-alanine ethyl ester in hydrochloride form and 1.83 ml of triethylamine in 30 ml of dichloromethane is stirred at room temperature for 10 minutes. Next, 2.05 g of quinoline-4-carbaldehyde are added. The reaction medium is stirred at room temperature for 15 hours and then concentrated under reduced pressure. 35 ml of ethanol are then added; the solution is cooled to 0° C. and 0.49 g of sodium borohydride is then added portionwise. Stirring is continued for 15 hours at room temperature. The precipitate formed is filtered off; the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column (SiO2, CH2Cl2/MeOH, 95/5 by volume as eluent, Ar). 0.71 g of ethyl (S)-2-[(quinol-4-ylmethyl)amino]propanoate is obtained in the form of a pink oil.
Reaction SMILES: O.S[C@@H:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5].C([O-])([O-])=[O:15].[K+].[K+]>CN(C=O)C>[O:11]=[CH:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:15])[OH:9])[OH:7])[OH:5]
Reactant: OC[C@H]1O[C@@H](S)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
0.2 g of Polymer 2 was dissolved in 8 ml of DMF in 25 mL single-neck round bottom flask. 0.2 g of 1-thio-β-D-glucose was added, following by 0.5 g of anhydrous K2CO3. The reaction mixture was stirred at room temperature for 30 hrs, and then transferred into a dialysis tube for dialysis against water for 2 days (8 water changes). The solution obtained in dialysis tube was then transferred into a single-neck round bottom flask. After removal of water, Glucose-functionalized Polymer 2 was obtained as a black solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29]Br)[CH2:23]1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][O:15][N:14]=[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]2=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: ON=C1CCCCC1=Cc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 264 h
Yield: 35.3 %

Procedure:
A mixture of the above oxime (3.7 g, 18.4 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (7.0 g, 20.2 mmol, EP 374801), potassium carbonate (10.2 g, 73.5 mmol) and acetone (150 ml) was stirred at ambient temperature for 11 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g, heptane/ethyl acetate=3/2) to give 2.5 g of (R)-1-(2-(((2-(benzylidene)cyclohexylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([O-:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:12]([CH2:13][C:14]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])=[O:16])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 g of N-methyl o-nitro aniline and 70 g of monoethyl malonate (obtained according to M. FREUND, Ber. 17, 780, 1 884) are dissolved in 550 c.C. of benzene, the solution is agitated and 106 g of phosphorus pentachloride are added, while maintaining the temperature at 20°-23° C; this is agitated for three hours at room temperature, then heated for one hour at 70° C; an yellow precipitate forms, which dissolves again, giving an orange solution; a water-ice mixture is added, while agitating, to obtain a volume of 1,500 c.c., keeping the temperature at 30° C; the benzene phase is decanted off, washed with water, then with a saturated aqueous solution of sodium bicarbonate and finally with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is purified by recrystallisation in the xylol-petroleum ether mixture (2,5-1). The compound melts at 54°-55° C. Analysis: C12H14N2O5 = 266.25; Calculated: C % 54.13; H % 5.30; N % 10.52; Found: 54.02; 5.23; 10.77.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3/[C:10](=[CH:11]/[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])/[C:4]=2[CH:3]=1>Cl.CO>[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3/[C:10](=[CH:11]\[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])/[C:4]=2[CH:3]=1
Reactant: CN(C)CC/C=C1/c2ccccc2COc2ccc(O)cc21
Agent: Cl
Solvent: CO
Product: CN(C)CC/C=C1\c2ccccc2COc2ccc(O)cc21
Temperature: 140 °C

Procedure:
A mixture of (Z)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin (2.5 mg, 8.5×10−6 mol) was dissolved in a mixture of hydrochloric acid (1 mL) and methanol (9 mL) and heated at 140° C. (oil bath) for 4 hr. The product was isolated by means of HPLC and evaporation of solvents.
Reaction SMILES: C(OC([C:8]1[N:12]([CH2:13][C:14]([O:16]CC)=[O:15])[N:11]=[N:10][N:9]=1)=O)C(C)C.Cl>O>[N:12]1([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[N:9][N:10]=[N:11]1
Reactant: CCOC(=O)Cn1nnnc1C(=O)OCC(C)C
Agent: Cl
Solvent: O
Product: O=C(O)Cn1cnnn1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
The crude 5-(isobutoxycarbonyl)-1H-tetrazole-1-acetic acid, ethyl ester prepared above was treated with 37.5 ml. (0.45 moles) of concentrated hydrochloric acid and 37.5 ml. of water in a 250 ml. 3-neck round bottom flask. The reaction mixture was heated to reflux, and the alcohols liberated as by-products of the reaction were allowed to distill out and carbon dioxide was permitted to evolve. Water was added as required during the reaction to maintain the volume in the flask at approximately 110 ml. When the distillation of the alcohols had ended, the mixture was treated with approximately 1 ml. of nitric acid to decolorize the solution. The solution was then cooled to approximately 70° C. and treated with charcoal. The solution was stirred for approximately 20 minutes and filtered hot into a clean 250 ml. 3-neck round bottom flask, washing with a minimum of water. The volume of the solution was reduced to approximately 120 ml. by distillation in vacuo and the mixture cooled. The precipitated solid was collected by filtration to afford 46.48 grams (98.1% pure) of 1H-tetrazole-1-acetic acid (m.p. 128.5°-130° C.). The overall yield of the synthesis from ethyl chloroacetate was 80.6% in the first cycle. When the 1H-tetrazole-1-acetic acid mother liquor was used as the solvent for the hydrolysis reaction in subsequent batches, the average yield of product over 9 cycles was 93.1%, with an average assay of 98.5% purity. The mother liquor was discarded after 9 cycles due to the salt accumulation.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN(CC)CC.N#N>O1CCOCC1>[Cl:12][C:11]1[C:2]([NH:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)CC(O)CN
Reactant: Clc1nc2ccccc2nc1Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CC(O)CNc1nc2ccccc2nc1Cl
Temperature: 25 °C
Yield: 47.8 %

Procedure:
2,3-Dichloroquinoxaline (18.05 g, 90.7 mmol) is added to a solution of crude 1a (11.7 g, 99.8 mmol) and Et3N (19 ml, 13.8 g, 136 mmol) in dioxane (210 ml). The solution obtained is heated at reflux (under N2) for 6 h, it is then cooled to room temperature. Et3N, HCl is eliminated by filtration and the filtrate is concentrated under reduced pressure. The dark orange residue is purified by chromatography on a silica column, eluent: CH2Cl2/MeOH (100:0→99:1), to obtain a yellow solid (12.14 g, 48%); 1H NMR (100 MHz, CDCl3) δ: 0.72 (d, 3H), 0.78 (d, 3H), 1.60 (m, 3H), 3.68 (m, 4H), 5.82 (t, 1H), 7.58 (m, 4H); 13C NMR (25 MHz, CDCl3) δ: 22.17, 23.35, 24.60, 44.32, 48.62, 69.67, 125.30, 125.62, 127.91, 130.36, 136.52, 137.92, 140.59, 148.62. Analysis calculated for C14H18N3OCl: C, 60.10; H, 6.49; N, 15.02. Experimental: C, 59.87; H, 6.62; N, 15.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:67]([CH2:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]1)[CH3:68])[CH2:64][CH2:65][CH3:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][N:67]([CH2:63][CH2:64][CH2:65][CH3:66])[CH3:68])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCCCN(C)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCN(C)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-butyl-N-methyl-C-(piperidin-2-yl)-methylamine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24](O)=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:51][C:52]([F:59])([F:58])[C@H:53]1[CH2:57][CH2:56][CH2:55][NH:54]1.C(N(CC)CC)C>CN(C)C=O.O>[F:28][C:2]([F:27])([F:1])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24]([N:54]3[CH2:55][CH2:56][CH2:57][C@@H:53]3[C:52]([F:59])([F:58])[F:51])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(F)(F)F)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 8-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11h) (62 mg, 0.187 mmol) in dimethylformamide (0.6 ml) was added 1-hydroxybenzotriazole (28 mg, 0.206 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.206 mmol). The mixture was stirred for 3 h at 50° C., then (R)-2-trifluoromethyl-pyrrolidine (42 mg, 0.206 mmol) and triethylamine (38 mg, 0.37 mmol) were added and the mixture was stirred at 25° C. for 24 h. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and dried in vacuo to give 66 mg (68%) of 6-((R)-2-trifluoromethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 5): Rt=4.55 min; m/z=519.13 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:21]=[C:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[F:18][C:19]([F:34])([F:35])[C:20]1[CH:21]=[C:22]([CH2:30][C:31]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:32])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 38.1 %

Procedure:
Example 17 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and [3,5-bis(trifluoromethyl)phenyl]acetic acid (0.054 g) to give the title compound (0.04 g).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][OH:37]>[Cu]I.C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:37][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)=[CH:23][CH:24]=1
Reactant: OCc1ccccn1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2ccccn2)cc1
Temperature: 110 °C
Reaction time: 22 h
Yield: 55.7 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), 1,10-phenanthroline (36 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (652 mg, 2.0 mmol, 2.0 equiv), 4-iodoanisole (234 mg, 1.0 mmol, 1.0 equiv), 2-pyridylcarbinol (193 μL, 2.0 mmol, 2.0 equiv) and toluene (0.5 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 22 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:diethyl ether 1:1) provided 120 mg (56% yield) of the title compound as a light yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=3[CH3:25])[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2,3-Dimethylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.04 (t, 1H), 6.99 (m, 2H), 5.38 (s, 2H), 3.64 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.21 (m, 9H) ppm; MS (ES) M+H expect 415.1, found 415.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.O.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.Br[CH2:17][CH2:18][CH:19]1[O:24][CH2:23][CH2:22][CH2:21][O:20]1>C(#N)C>[O:20]1[CH2:21][CH2:22][CH2:23][O:24][CH:19]1[CH2:18][CH2:17][N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: O=C1CCNCC1
Reactant: BrCCC1OCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCN(CCC2OCCCO2)CC1
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Sodium carbonate (17.4 g, 125.9 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (6.45 g, 42.0 mmol) in acetonitrile (200 mL). After 30 minutes stirring at rt a solution of 2-(2-bromoethyl)-1,3-dioxane (8.45 g, 43.3 mmol) in acetonitrile (50 mL) was added dropwise to the reaction mixture and stirring was continued overnight at rt and at reflux for an additional 2 hours. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 7% methanol in dichloromethane, afforded 1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one (6.19 g, 69%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:24])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:6])=[O:7]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N(CCO)CCBr)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-{[(2-bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-hydroxy-1H-indole-2-carboxamide, described in Step B of Example 51, in 2:1 dichloromethane/MeOH was added excess trimethylsilyldiazomethane (solution in hexane). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the titled product. HRMS (ES) exact mass calculated for C14H18BrN3O5S (M+H+): 420.0224. Found 420.0221.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1CC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc([N+](=O)[O-])cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethoxy-2-ethyl benzene (3.5 g, Reference Example 51) in acetic anhydride (30 mL) was chilled in an ice-water bath. A solution of nitric acid (1.4 mL of 90%-30% excess) in acetic acid (25 mL) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice water (300 mL) and the aqueous mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane with gradient of 5 to 10% ethyl acetate) to give 1-ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a clear liquid. LC-MS (Method E) RT=3.75 minutes, 196 (M+H)+. (i) N-(5-Chloro-4-methoxy-2-nitrophenyl)acetamide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[K+].[C:24](=S)=[S:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:24]([SH:25])=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-1H-benzimidazole-6-carbohydrazide (1.09 g, 3.86 mmol), potassium hydroxide (0.32 g, 5.79 mmol), carbon disulfide (2.31 mL, 38.6 mmol) and ethanol (20 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, N,N-dimethylformamide (15 ml) was added to the residue, and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with water to give the title compound (0.66 g, yield 53%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC=C(C(F)(F)F)C=2)=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1.O1CCOCC1.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 100 °C
Yield: 76.2 %

Procedure:
To N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide (442 mg, 0.990 mmol) was added 1,4-dioxane (2.0 mL) and water (2.0 mL) and sodium hydroxide (790 mg, 19.8 mmol). The resulting mixture was heated to 100° C. until LCMS indicated complete hydrolysis, typically 14-16 hours. The reaction was cooled to ambient temperature and the solvents were removed by evaporation. The residue was washed with water and the remaining solid was recovered by filtration, washed with additional water, and dried under reduced pressure to give the product (207 mg, 76%). 1H NMR (300 MHz, DMSO): δ 9.42 (s, 1H), 8.90 (s, 1H), 8.22 (d, 1H), 7.39 (s, 1H), 7.23 (d, 1H), 6.94 (d, 1H), 6.52 (m, 2H), 4.95 (s, 2H), 2.08 (s, 3H). MS (EI) m/z=275 (M+H).
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C@@H:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].Cl>O>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: Cl
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
By dissolving 20 g of the resulting crystalline (6S)-tetrahydrofolic acid in 80 ml of water at pH 9 and subsequently slowly bringing the pH to 5.1 using hydrochloric acid, 4.5 g of crystalline (6S)-tetrahydrofolic acid with a chemical content of 94.0% and a (6S) percentage of 94.7 are obtained after seeding with crystalline (6S)-tetrahydrofolic acid. The water content after drying is 1.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([C:13]#[CH:14])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 95.9 %

Procedure:
274.4 g of 4-(trimethylsilylethinyl)-benzoic acid tert.-butyl ester and 12.5 g of anhydrous potassium carbonate in 1.5 l of absolute methanol are stirred together for 3 hours under nitrogen. The reaction mixture is then concentrated by evaporation and worked up with CH2Cl2 /H2O to yield 194 g of 4-ethinyl-benzoic acid tert.-butyl ester.