Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[C:1]([Cl:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
A solution of 20.0 g of linolic acid in 70 ml of dry benzene was placed in a flask and kept swept therein with nitrogen for displacement of the entrapped air and 14.8 g of phosphorus pentachloride was added meanwhile thereto as divided in five split portions. The resultant reaction mixture was stirred at normal room temperature for 12 hours and then refluxed for two hours. Then, the reaction solution was distilled to expel benzene and the products of a secondary reaction, i.e. phosphoryl trichloride and hydrogen chloride and the residue was subjected to vacuum distillation to produce 14.0 g of linolic acid chloride (boiling point 155° C./1.5 mmHg; yield 76%).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([CH:6]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)=[O:5])[CH3:2].C(OCC)(=O)C>C(O)C.[C].[Pd]>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:22]
Reactant: CCN(CC)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 31 (556 mg) was dissolved in ethanol (10 mL) and ethyl acetate (20 mL) and added with 5% palladium carbon (100 mg) and the reaction solution was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction solution was filtered with celite and the solvent was distilled off to give the titled compound having the following physical properties. The resulting titled compound was used for the next reaction without further purification.
Reaction SMILES: C1(CC(Cl)=O)CCCCC1.[CH:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:11]1([CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[CH:39][CH:40]=2)=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CC1CCCCC1)N=C=S
Agent: O=C(Cl)CC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CC4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Cyclohexylethanoyl isothiocyanate was prepared using commercially available 2-cyclohexylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Cyclohexylethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH2:34].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([CH2:34][CH2:33][S:35]([CH3:38])(=[O:37])=[O:36])[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: C=CS(C)(=O)=O
Agent: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of (S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (1.5 g, 3.47 mmol) in anhydrous DMF (20 mL) is cooled down to 0° C. in an ice bath when NaH (194 mg, 60% in mineral oil, 4.86 mmol) is added into the solution portion wise. After the addition, the mixture is stirred at 0° C. for 10 min when a solution of vinyl methylsulfone (736 mg, 6.94 mmol) in DMF (5 mL) is added into the mixture. The resulted mixture is allowed to warm up to room temperature and stir for 1 h. The mixture is then poured into 10% NH4Cl aqueous solution (˜300 mL) and extracted with EtOAc (3×100). The combined organic layer is washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0%˜100%) to provide the desired product (S)-3-[4-(4-chloro-phenoxy)-phenyl]-1-(2-methanesulfonyl-ethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one as white solid (1.18 g, 63%) with the recovery of the starting material (S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (˜300 mg). 1H NMR (CDCl3, 400 MHz) δ 7.45˜7.58 (m, 4H), 7.29 (d, 2H), 7.23 (d, 2H), 6.87 (m, 4H), 5.27 (dd, 1H), 4.07 (t, 1H), 3.80˜4.10 (m, 2H), 3.28˜3.40 (m, 3H), 3.01 (s, 3H); HPLC-MS calculated for C25H22ClF3N2O4S (M+H+) 539.1, found 539.1.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[S:16][C:15]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[S:16][C:15]([CH2:17][C:18]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)s1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccc(F)cc3)s2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-(4-fluoro-phenoxy)-thiophen-2-yl)-acetohydroximoyl chloride (250 mg, 0.875 mmol) described in Manufacturing Example 91-1-4 and 3-ethynyl-pyridin-2-ylamine (50.0 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (177 μL, 1.27 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2→1:1) to obtain the title compound (11.2 mg, 7.21%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[CH:20][C:19]=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[C:21]([O:25][CH3:26])[C:22]([CH3:24])=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(I)c(F)cc1C
Product: CCSc1ncc(C(=O)c2cc(OC)c(C)cc2F)c(N)n1

Procedure:
The same procedure as described in Example 376 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 1-fluoro-2-iodo-4-methoxy-5-methyl-benzene (Example 382) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone. MS (M+H)+, 322.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:12].C(Cl)(Cl)Cl>O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([CH:6]([OH:12])[CH2:1][CH2:2][CH3:3])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: c1ccc(-c2ccsn2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCC(O)c1cc(-c2ccccc2)ns1
Reaction time: 1 h

Procedure:
Dissolved in 60 ml of anhydrous tetrahydrofuran were 3.1 g (19.1 mmol) of 3-phenylisothiazole, followed by the addition 18.2 ml of an n-butyl lithium-hexane solution (1.57 mol/l) under a nitrogen gas stream at -78° C. over a dry ice-acetone bath. After the resulting mixture was stirred for 1 hour, 1.51 g (21 mmol) of butylaldehyde were added dropwise. The solution was stirred for 1 hour at the same temperature, whereby the reaction was completed. Water and chloroform were added. The reaction product was extracted into an organic layer. The organic layer was concentrated and the concentrate was purified by silica gel chromatography (eluent: 20:1 n-hexane/ethyl acetate), so that 3-phenyl-5-(1-hydroxybutyl)isothiazole was obtained as yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.C(Cl)Cl.[OH-].[Na+].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40]O>>[OH:23][C@H:3]1[C@H:2]([O:1][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: COCCOCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCOCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 50 °C

Procedure:
5 g of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]-naphthyridine are dissolved in 40 ml of 2-(2-methoxyethoxy)ethanol, 3.2 g of sulfuric acid (98% strength) are added and the mixture is warmed at 50° C. for 16 hours. It is then poured onto ice, 100 ml of methylene chloride are added and the mixture is adjusted to pH 7 using aqueous 8 N sodium hydroxide solution. After separation of the organic phase, the aqueous phase is extracted a further two times using 50 ml of methylene chloride each time, the combined organic phases are washed with 100 ml of water, dried over sodium sulfate and the solvent is stripped off in vacuo. The residue is purified on silica gel (eluent: diethyl ether/2-propanol=10/1). 105 mg of the title compound are obtained. 1H-NMR (200 MHz, DMSO): δ=2.25 (s, 3H), 2.33 (s, 3H), 3.23 (s, 3H), 3.32-3.47 (m, 6H), 3.59-3.69 (m, 2H), 3.97-4.07 (q, 1H), 4.44-4.47 (m, 2H), 5.18-5.21 (d, 1 OH), 5.85-5.86 (d, 1NH), 6.74-6.78 (d, 1H), 7.19-7.45 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])(=[S:20])[NH2:2]
Reactant: S
Reactant: N#Cc1cccc2c1CCC2=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cccc2c1CCC2=O
Reaction time: 16 h

Procedure:
A solution of 12.1 g (77 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one [see Coll. Czechoslov. Chem. Commun. 4, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated with hydrogen sulfide for 3 hours at 40° and is then stirred at the same temperature for 16 hours. The reaction mixture is cooled and then concentrated to dryness by evaporation, and 300 ml of water are added to the residue. The yellow product that has crystallized out is filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. In that manner there is obtained the title compound, m.p. 197° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(Cl)cc3nc(C(=O)O)cn3c2c1
Temperature: 25 °C

Procedure:
600 mg of ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in 100 ml of 50% aqueous ethanol and then 4.4 ml of N sodium hydroxide solution were added. The mixture was heated on a steam bath for 1 hour and the resulting solution was acidified with 4.4 ml of N hydrochloric acid and then was cooled to room temperature to obtain colorless crystals of 5-chloro-8-methoxy-imidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 277°-278° C.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.O1CCOCC1.O.[F-].[Cs+].[C:34]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37][CH2:36][CH:35]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:34]4[CH2:38][CH2:37][CH2:36][CH:35]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCCC3)ccc12
Yield: 4.1 %

Procedure:
2,6-Dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (300 mg, 0.74 mmol, 1.00 eq) in 1,4-Dioxane (6 mL, 69.44 mmol, 20 V)/Water (2 mL, 111.02 mmol, 6.67 V) was taken in a microwave vial and to this were added Cesium fluoride (338.80 mg, 2.23 mmol, 3.00 eq) and 2-Cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (172.97 mg, 0.89 mmol, 1.20 eq). The reaction mixture was purged with nitrogen for 15 min and bis(triphenyl phosphine)palladium (II) dichloride (25.16 mg, 0.04 mmol, 0.05 eq) was added and heated under microwave at 130 OC for 1 h. The reaction mixture was concentrated and the crude obtained was purified by flash column chromatography to afford the title compound (12 mg, 0.03 mmol, 3.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, J=5.64 Hz, 1H), 7.95-7.98 (m, 3H), 7.75 (d, J=9.0 Hz, 1H), 6.88 (s, 1H), 3.26-3.29 (m, 2H), 2.85-2.89 (m, 2H), 2.60 (s, 2H), 1.96-2.04 (m, 4H), 1.81-1.86 (m, 3H), 1.74-1.77 (m, 2H), 1.23-1.33 (m, 2H). m/z: 405 [M+H]+
Reaction SMILES: ClC1(Cl)[C@@H]2[C@@H](CCC=C2)C1=O.[CH3:12][O:13][C@@:14]12[C:21](=[O:22])[CH2:20][C@@H:19]1[CH:18]=[CH:17][CH2:16][CH2:15]2>>[CH3:12][O:13][C@:14]12[C:21](=[O:22])[CH2:20][C@H:19]1[CH:18]=[CH:17][CH2:16][CH2:15]2
Reactant: CO[C@]12CCC=C[C@H]1CC2=O
Agent: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Product: CO[C@@]12CCC=C[C@@H]1CC2=O

Procedure:
Similarly, starting with (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, prepared as shown in Preparation 22, in place of the racemic compound in Preparation 2.A. above, (1S,6S)-6-methoxybicyclo[4.2.0]oct-2-en-7-one is prepared. Similarly, starting with the (1R,6S)-compound, (1R,6R)-6-methoxybicyclo[4.2.0]oct-2-en-7-one is prepared.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1>N.[Ni]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Agent: [Ni]
Agent: N
Product: COC(=O)c1cc(CN)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
A mixture of 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.37 g, 0.92 mmol) in NH3 saturated MeOH (10 mL) was treated with Raney nickel (0.50 g), and placed under 50 psi H2 on a Parr shaker, for 18 h. The mixture was filtered through celite and the cake was washed with methanol. The eluant was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 0.177 g (47%) of 5-aminomethyl-2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:37]([CH3:39])[CH3:38])C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:38][N:37]([CH3:39])[C:11]([C:9]1[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(C(=O)N(C)C)cc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (80 mg, 0.30 mmol), BOP (159 mg, 0.36 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) in DMF (3 mL) is added 0.164 mL of 2 N dimethylamine in THF solution at room temperature. The mixture is stirred at room temperature for 3 h, quenched with 1N NaOH aqueous solution, and extracted with EtOAc. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, 5% MeOH in CH2Cl2) to give 64 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:32][CH2:33]Cl)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[CH2:32][CH2:33]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(CN(CCCl)CCCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Yield: 54.4 %

Procedure:
A solution of 4.2 g (16.5 mmol) of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.95 g (16.5 mmol) of bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine in 25 ml of N,N-diisopropylethylamine is heated at 127° C. for 6 h. After evaporation of a maximum amount of diisopropylethylamine, the reaction medium is diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide having a concentration of 1N. The organic phase obtained is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 4.0 g (55%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)-piperazin-1-yl]propanoate are obtained in the form of an oil.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O.C(O)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OCC(CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a stirring solution of N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.907 g, 1.74 mmol) in methanol (10 mL) and water (1 mL) at ambient temperature was added p-toluene sulfonic acid (0.032 g, 0.17 mmol). After stirring for 18 hours the reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with water and once with saturated brine solution. Organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo affording a light brown solid, which was dissolved in ethanol and precipitated with water to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as a white solid (0.387 g). m.p.=83-85° C.; 1NMR (400 MHz, DMSO-d6) 11.87 (s, 1H), 8.69 (s, 1H), 7.56 (d, 1H, J=11.0), 7.33-7.39 (m, 2H), 7.19 (dd, 1H, J=16.6, 9.0), 6.62-6.68 (cm, 1H), 4.82 (d, 1H, J=4.2), 4.58 (t, 1H, J=5.5), 3.84-3.87 (m, 1H), 3.66-3.72 (m, 2H), 3.3 (2H, partially hidden by HDO); MS(APCI+)=483.0; Anal. calcd/found for C16H14F3IN2O4.0.3H2O: C, 39.41/39.02; H, 3.02/2.93; N, 5.75, 5.81; F, 11.69/11.68.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][NH:31][C:32](=[O:36])[C:33](O)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33]([C:32]([NH:31][CH3:30])=[O:36])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CNC(=O)C(=O)O
Product: CNC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(methylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 34 mg (55%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[N:6][N:5]=1.I[CH2:16][CH3:17]>CN(C=O)C>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:16][CH3:17])[N:5]=1
Reactant: Oc1nnc(Cl)c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(Cl)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil, (0.480 g, 12.00 mmol) in DMF (50 mL) was added 4-chlorophthalazin-1-ol (1.806 g, 10 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of iodoethane (2.339 g, 15.00 mmol) in DMF (50 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The formed light yellow solid was filtered off and washed the cake with THF. The filtrate was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by silica gel chromatography eluting with 20% EtOAc in hexanes to afford 1.8 g of the desired product 4-chloro-2-ethylphthalazin-1(2H)-one as an oil. MS: MS m/z 209.06 (M++1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52-8.42 (m, 1H), 8.04-7.98 (m, 1H), 7.88 (dtd, J=18.5, 7.5, 1.5 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).