Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14]Br)[CH2:2][CH2:3][CH3:4].[CH:16]([NH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C1(C)C=CC=CC=1>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:19]([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)NC(C)C
Reactant: CCCCOc1ccccc1OCCBr
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccccc1OCCN(C(C)C)C(C)C
Yield: 53.5 %

Procedure:
The thus obtained 1-n-butoxy-2-(2'-bromoethoxy)-benzene (2.73 g, 10 mmole) was heated under reflux for 160 hours with diisopropylamine (4.0 g; 40 mmole) and toluene (25 ml). The reaction mixture was shaken with water until the precipitated salt had dissolved. The toluene phase was then extracted with an excess of dilute hydrochloric acid. The extracts were washed twice with ether and then made alkaline with sodium hydroxide solution. The precipitated base was taken up in ether and the aqueous phase extracted once more with ether. The ether extracts were washed once with water and then dried over potassium carbonate. The solvent was evaporated and the residue distilled to yield 1.57 g (53.5%) of product with b p 104°-105° C at 0.02 mm Hg; nD25 = 1.4936.
Reaction SMILES: O.Cl.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)#N.Cl>CO.O>[CH2:5]1[S:6]/[C:12](=[C:14]2/[N:18]=[C:17]3[C:16]([S:15]/2)=[CH:22][C:21](=[O:23])[CH:20]=[CH:19]3)/[NH:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
685 mg. (3.9 mMol) D-cysteine hydrochloride monohydrate are dissolved in 13 ml. water which has been previously gassed with nitrogen. A pH value of 8 is adjusted, under an atmosphere of nitrogen, with about 6 ml. of a 1N aqueous sodium hydroxide solution and then a solution of 528 mg. (3 mMol) 2-cyano-6-hydroxybenzothiazole in 22 ml. methanol (analytically pure) is added thereto under an atmosphere of nitrogen. The yellow solution is stirred under an atmosphere of nitrogen and with the exclusion of light for 1 hour at ambient temperature. Subsequently, the solution is acidified with 3 ml. of 2N hydrochloric acid and left to stand for about 3 hours at 4° C. The precipitated crystals are filtered off with suction under an atmosphere of nitrogen, washed with methanol and water (1:1 v/v) and dried in a desiccator with the exclusion of light. 0.75 g. D-Luciferin are obtained, which corresponds to a yield of 89.3% of theory. The compound melts at 187°-188° C., with decomposition, and is chromatographically identical with the product known from the literature but contains small amounts of impurities.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C@@H:5]([C:15]([O:17]C)=O)[CH2:4]1.[NH3:19]>CO>[ClH:13].[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C@@H:5]([C:15]([NH2:19])=[O:17])[CH2:4]1
Reactant: COC(=O)[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@@H](N)C1
Reactant: N
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@@H](N)C1

Procedure:
Into a solution of 3.6 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride in 50 ml of methanol and 15 ml of 28% aqueous ammonia, ammonia gas is blown at 30°-40° C. for 8 hours. The solvent is distilled off and water is added. The precipitated crystals are separated by filtration and dissolved in methanol and to the solution is added methanolic hydrochloric acid. Crystals are deposited, separated by suction filtration and recrystallized from methanol to give 1.6 g of trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthalene carboxamide hydrochloride having a m.p. of above 280° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[C:11]([CH2:20]O)=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2>ClCCl>[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[C:11]([CH2:20][Cl:3])=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Thionyl chloride (2 mL) was added to a solution of 2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionic acid methyl ester (245 mg, 0.59 mmol) in dichloromethane (3 mL). Mixture was stirred at room temperature for 1.5 hours. Mixture was concentrated. Residue was dissolved in dichloromethane (15 mL) then washed with saturated aqueous sodium bicarbonate (2×10 mL). Organic was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as an orange solid in 86% yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.19 (s, 1H), 7.32 (m, 5H), 7.16 (s, 1H), 5.49 (d, J=7.3, 2H), 5.07 (d, J=4.4, 2H), 4.85 (s, 2H), 4.68 (d, J=7.0, 1H), 3.72 (s, 3H), 3.27 (m, 2H). MS m/e (M+H)+=436.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][N:28]=[C:27]2[NH:35][CH:36]=[C:37]([NH:38][C:39](=[O:44])[C@H:40]([O:42][CH3:43])[CH3:41])[C:26]=12>CCCCO.O>[CH3:43][O:42][C@H:40]([CH3:41])[C:39]([NH:38][C:37]1[C:26]2[C:27](=[N:28][CH:29]=[C:30]([C:31]([F:34])([F:32])[F:33])[C:25]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:35][CH:36]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Solvent: O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 41 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (456 mg, 2.28 mmol) and N,N-diisopropylethylamine (294 mg, 0.396 mL, 2.28 mmol) were added to a suspension of (R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (244 mg, 0.759 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube under a nitrogen atmosphere at 160° C. for 24 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give tert-butyl (R)-1-(3-((R)-2-methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (151 mg, 41%) as a solid. LCMS (APCI+) m/z 386.1, 486.1 (M+H)+, Retention time=3.85 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11](=[O:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[I:51]I>O1CCCC1>[I:51][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[P:11](=[O:24])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: II
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)c(I)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
db) 3.38 g (10 mmol) of (3,4-dimethoxyphenyl)diphenylphosphine oxide and 50 ml of dry tetrahydrofuran were placed in a 0.3 l four-necked sulphonation flask provided with a stirrer, thermometer, dropping funnel and argon gasification. In a separate Schlenk tube 8.0 ml of 1.6N butyllithium solution in hexane (12.8 mmol) were added dropwise under argon and while stirring at -78° C. to a solution of 1.57 g (15.5 mmol) of diisopropylamine in 10 ml of tetrahydrofuran and the solution was stirred at 0° C. for a further 10 minutes. The thus-prepared lithium diisopropylamide solution was then transferred into the dropping funnel of the reaction apparatus and then added dropwise at about -75° C. to the (3,4-dimethoxyphenyl)-diphenylphosphine oxide solution. The resulting pink suspension was stirred at -78° C. for a further 2 hours. Then, it was treated dropwise at <-70° C. with a solution of 3.3 g (13 mmol) of iodine in 20 ml of tetrahydrofuran. Towards the end of the addition there formed a viscous paste which was difficult to stir and which again dissolved when subsequently left to warm to room temperature. The reaction solution was washed 3 times with 20 ml of saturated Na2S2O3 solution each time and once with saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue (5 g) was chromatographed on 200 g of silica gel with ethyl acetate and the resulting product was recrystallized from tert.-butyl methyl ether. There were obtained 3.8 g of (2-iodo-3,4-dimethoxyphenyl)-diphenylphosphine oxide as a light beige crystallizate : m.p. 178.5°-179.5° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1O[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[OH-].[NH4+:13]>CO>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:13]=1
Reactant: [NH4+]
Reactant: O=c1ccoc(C(F)(F)F)c1
Agent: [OH-]
Solvent: CO
Product: Oc1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 80.6 %

Procedure:
To a solution of 2-(trifluoromethyl)-4H-pyran-4-one (350 mg, 2.13 mmol) in MeOH (15 mL) was added ammonium hydroxide (14.8 mL, 107 mmol) at 25° C. The reaction mixture was stirred at 90° C. for 10 h, then concentrated, diluted with water and extracted with ethyl acetate. Combined organic parts were dried over Na2SO4, filtered and con. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3, CH3CN/water, 10˜95%, 9.5 min, 30 mL/min) afforded the title product (280 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C@H:23]3[C:32]4[C:27](=[C:28]([O:33][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:69]([O:72][CH2:73][CH3:74])(=[O:71])[CH3:70]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C@H:23]3[C:32]4[C:27](=[C:28]([O:33][CH2:70][C:69]([O:72][CH2:73][CH3:74])=[O:71])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g) in THF (20 ml) was added tetrabutylammonium fluoride (2.7 ml, 1M solution in THF) at 0° C. After being stirred for 2 hours at the room temperature, the mixture was diluted with ethyl acetate and washed with water and brine. The dried solvent was evaporated in vacuo. The obtained oil was dissolved into DMF (10 ml) and then K2CO3 (2.0 g) and ethyl bromoacetate (0.3 ml) were added at room temperature. The mixture was stirred for 2 hours at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalene (800 mg).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1>>[C:1]([O:20][CH2:21][CH2:22][NH:23][C:36](=[O:37])[CH2:35][CH2:34][NH:33][C:31]([CH:29]1[C:28]([CH3:39])([CH3:40])[CH2:27][O:26][C:25]([CH3:41])([CH3:24])[O:30]1)=[O:32])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 30.9 %

Procedure:
2-Aminoethyl oleate (3.26 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 1.75 g of the title compound (yield: 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([CH:31]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]([O:28]CC)=[O:27])[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([CH:31]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]([OH:28])=[O:27])[N:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4F)CC3)nc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4F)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 5) from ethyl (5-{2-[4-(5-bromo-2-fluorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetate and aqueous NaOH.
Reaction SMILES: C(ON=O)(C)(C)C.[CH2:8]([Br:11])[CH:9]=[CH2:10].Br[C:13]1[CH:19]=[CH:18][C:16](N)=[CH:15][CH:14]=1.NC1C=CC=CC=1>CC#N>[CH2:15]([C:14]1[CH:13]=[CH:19][C:8]([Br:11])=[CH:9][CH:10]=1)[CH:16]=[CH2:18]
Reactant: C=CCBr
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=CCc1ccc(Br)cc1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-bromoaniline (516 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 30-35° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 30° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (pentane) gave 200 mg (34%) of 4-allylbromobenzene as a clear oil. 1H NMR (CDCl3, 400 MHz) δ 7.43, (m, 2H, J=8.3 Hz), 7.08, (m, 2H, J=8.3 Hz), 6.00-5.89, (m, 1H), 5.12-5.05, (m, 2H), 3.35, (d, 2H, J 6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 139.4, 137.2, 131.9, 130.8, 120.3, 116.7, 40.0; Anal HRMS Calcd. for C9H9Br (M): 195.9888. Found: 195.9887.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33]>>[CH3:31][S:32]([CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][C:20]1[N:21]=[C:17]([NH:16][C:15]([NH:14][C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[O:2][CH3:1])=[O:26])[S:18][CH:19]=1)(=[O:34])=[O:33]
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CS(=O)(=O)CCN
Product: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)NCCS(C)(=O)=O)cs1
Yield: 68.2 %

Procedure:
N-(2-Methanesulfonyl-ethyl)-2-(2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetamide (181 mg, 68%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 2-methanesulfonyl-ethylamine (61 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([N:8](CC)[CH2:9][CH3:10])[CH3:7].C(NCC)C>CCCCCC>[CH2:6]([N:8]([Si:2]([CH3:5])([CH3:4])[CH3:1])[CH2:9][CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCNCC
Product: CCN(CC)[Si](C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
In a 1 liter four-neck flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer were placed 108.5 g (1.0 mol) of trimethylchlorosilane, 111.1 g (1.1 mol) of triethylamine and 300 ml of hexane. Thereto, 73.0 g (1.0 mol) of diethylamine was added dropwise from the dropping funnel over a 1-hour period. During the addition, the temperature of the reaction system was kept within the range of 20° C. to 60° C. to make the reaction be proceeding. At the conclusion of the addition, the temperature was raised to 50-60° C. and kept there for 2 hours, whereby the reaction was matured. Then, the reaction mixture was filtered through a glass filter to remove the salt yielded as a by-product. The filtrate was allowed to stand for one day at room temperature to precipitate the salt. The salt precipitated was filtered off, and the filtrate was subjected to distillation under ordinary pressure to obtain 136.3 g of diethylaminotrimethylsilane as a fraction having a boiling point of 125-126° C. The yield was 94%, and the chlorine concentration was 146 ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(-c6ccccc6F)nc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(-c6ccccc6F)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (65 mg, 116 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (497 μg, 1.16 μmol, Eq: 0.01) were combined with Ethanol (853 μl) and Water (853 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. Mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (61 mg, 91%, [M+H]+ 580).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[N+:7]([C:10]1[CH:28]=[CH:27][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:26][C@H:24]([OH:25])[CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCl>[OH:25][C@H:24]1[CH2:26][N:18]([C:16]([O:15][CH2:14][C:13]2[CH:27]=[CH:28][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)=[O:17])[C@H:19]([C:20]([O:22][CH3:1])=[O:21])[CH2:23]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methanol (94.5 ml) and dichloromethane (945 ml) under ice cooling are dropwise added thionyl chloride (18.7 ml) and after 5 minutes stirring N-p-nitrobenzyloxycarbonyl-L-hydroxyproline (1:72.4 g) , and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuum to give crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.5 g) as pale yellow oil. This product can be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:28]([O:21][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OCc3ccccc3)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 17a, Step 3 (1.00 g, 3.10 mmole) in anhydrous DMF (10.0 mL) was added KI (51.5 mg, (0.310 mmole), K2CO3 (1.29 g, 9.30 mmole) and benzyl bromide (1.11 ml, 9.30 mmole). The suspension was stirred at room temperature for 2 h and poured into H2O (150 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (2×100 mL), dried over MgSO4 and concentrated in vacuo to give a yellow oil. Purification by silica chromatography (6:1 hexanes:EtOAc) gave 1.12 g (87.5% yield) of the product as a yellow crystalline solid: EIHRMS m/z 412.0689 (M+, C20H16ClF3O4, Calc'd 412.0680).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(=O)C(C)(C)C)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:28][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: NC1CCCCC1
Reactant: CC(C)OC(=O)C(C(=O)OC(=O)C(C)(C)C)=C1SC=CS1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)NC1CCCCC1)=C1SC=CS1

Procedure:
A solution of isoproyl 2-(1,3-dithiol-2-ylidene)-2-(pivaloyloxycarbonyl)acetate (13.2 g) and cyclohexylamine (3.97 g) in methylene chloride (100ml) was stirred at room temperature for 2 hrs. The reaction mixture was washed with aqueous sodium hydroxide solution and water and then evaporated to dryness. The resultant residue was recrystallized from ethyl acetate to afford the pure product. (12.0 g, 91.6%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[CH3:10][N:11](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1)#[N:11]
Reactant: CCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCc1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Argon was bubbled into a solution of 1-bromo-3-ethylbenzene (2.5 g, 13.5 mmol) in DMF (37 ml) for 10 min. and then zinc cyanide (1.75 g, 14.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.56 g, 1.35 mmol) were added. After stirring at 80° C. overnight the reaction mixture was diluted with ethyl acetate (35 ml) then filtered through celite to remove the precipitate. The filtrate was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by flash column chromatography using 2% ethyl acetate in hexane affording a colorless liquid (1.42 g). GC-MS (M+): 131.18.