Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2S[C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][C:21]=1[Cl:33].NCCC(O)=[O:38].CO.C(Cl)Cl>C(O)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:38][C:29](/[CH:31]=[C:3]3/[NH:4][C:5](=[S:18])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:2]/3=[O:1])=[CH:28][CH:27]=2)=[CH:22][C:21]=1[Cl:33]
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc(-c2ccc(Br)c(Cl)c2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)N1C(=O)/C(=C\c2ccc(-c3ccc(Br)c(Cl)c3)o2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.045 g, 0.175 mmol) and 5-(4-bromo-3-chloro-phenyl)thiophene-2-carbaldehyde (0.050 g, 0.175 mmol) in acetic acid 5 mL is added β-alanine (1.6 mg, 0.01 8 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075 g, 0.141 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:32])[F:31])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[NH2:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:32])[F:31]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl(12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-16-(dodecanoyloxy)-1,1-difluoro-11,19-dioxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile The resulting mixture was stirred at 25° C. until the smarting material disappeared. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([CH:36]=O)[NH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:28]([CH:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[O:24])[CH2:15][CH2:14]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC(C)c1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCCN1CCN(C)CC1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCCN1CCN(C)CC1
Yield: 44 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid [3-(4-methylpiperazin-1-yl)propyl]amide (300 mg) to give 65 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([C:28]([Cl:30])=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[ClH:30].[C:18]1([C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc5ccccc45)cc23)CC1
Product: Cl
Yield: 58.6 %

Procedure:
To a suspension of 1.2 gm (5.2 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 50 mL tetrahydrofuran were added 0.946 mL (6.3 mMol) 1-naphthoyl chloride dropwise. After 18 hours the reaction mixture was filtered. The recovered filtrate was dissolved in 10 mL dimethylformamide to which were added 1.5 mL (10.5 mMol) triethylamine followed by 0.8 mL (5.3 mMol) 1-naphthoyl chloride. After 18 hours the reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The phases were separated and the aqueous extracted again with ethyl acetate. The combined ethyl acetate extracts were then washed sequentially with 1N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was taken up in ethanol and treated with ethanolic hydrogen chloride. The solution was concentrated under reduced pressure and the residue crystallized from ethylacetate/ethanol to give 1.28 gm (58.2%) of the title compound as a tan powder.
Reaction SMILES: O.[Cl-:2].[OH:3][C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([C:12]#[C:13]/[C:14](/[CH3:36])=[CH:15]/[CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH3:37])[CH2:5]1.[H][H]>CO.OCCSCCSCCO>[Cl-:2].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([CH:12]=[CH:13][C:14]([CH3:36])=[CH:15][CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:6]([CH3:37])[CH2:5]1
Reactant: CC1=C(C#C/C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)C[C@H](O)C1
Reactant: [H][H]
Agent: OCCSCCSCCO
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C=CC1=C(C)CC(O)CC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A suspension of 46.6 g of water-moist Raney-nickel and 518 mg of 1,2-bis(2-hydroxyethylthio)ethane in 1 l of methanol was pre-hydrogenated at 30° C. under normal pressure in a sulphonation flask provided with a gasification stirrer. Subsequently, a solution of 320 g of (4R,2E)-[5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium chloride in 2.1 l of methanol was added thereto and the mixture was hydrogenated at 40° C. and 1.1 bar of hydrogen. 15.6 l of hydrogen were taken up within 5 hours. The catalyst was filtered off and the filtrate was concentrated to a weight of 575 g. The product was crystallized by slowly pouring in 9.6 l of ethyl acetate. The suspension was stirred at room temperature for 2 hours and filtered. The crystals were washed with a small amount of methanol/ethyl acetate and dried at 60° C./0.01 mbar, there being obtained 272.2 g (84.7%) of [5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienyl]triphenylphosphonium chloride (containing 97% of the (4R,2E,4Z)-isomer and 2% of the (4R,2Z,4Z)-isomer in accordance with HPLC) of melting point 211°-212° C. and [α]D20 =-26.2° (c=1, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH2:11]([C:18]1([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH2:6][CH2:5]3)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1(Cc2ccccc2)CCC(Nc2ccc3c(c2)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
266 mg 5-aminoindane and 462 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in dry 1,2-dichloroethane under argon and the solution was stirred with 2 g sodium sulfate for 24 hours at RT. 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for two hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate. 440 mg 1-benzyl-N′-indan-5-yl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a colorless oil. For preparation of the hydrochloride, the base was dissolved in 2-butanone (8 ml), and 1.85 M ethanolic hydrochloric acid (1.75 ml) was added. The solid which had precipitated out was filtered off with suction and dried. 280 mg 1-benzyl-N′-indan-5-yl-N,N-dimethyl-cyclohexane-1,4-diamine hydrochloride were obtained as a white solid (m.p. 200-203° C.)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>O.O1CCCC1>[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[NH:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CNC(=O)c1ccccc1I
Reaction time: 0.03 h
Yield: 21.9 %

Procedure:
A solution of 5.0 g of glycinamide hydrochloride in 10 ml of water was cooled in an ice bath during the addition of 30 ml of 6 N sodium hydroxide. To the resulting mixture was added a solution of 8.0 g o-iodobenzoyl chloride in 20 ml of tetrahydrofuran and the mixture was shaken vigorously for 2 minutes. The mixture was then stirred for 21/2 hours. The tan solid which formed was filtered by suction and washed with water until the washings were neutral. The residue was then dried on a rotary evaporator for 5 hours at 60° and 80 mm Hg. There was thus obtained a crude product which was recrystallized from ethanol to yield 2.0 g of o-iodohippuramide as buff colored crystals, m.p. 183°-185°, Rf 0.64.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (3.0 g, 0.01 mol) and benzenesulfonyl chloride (1.8 g, 0.01 mol) were dissolved in toluene (14.8 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (1.0 g, 0.01 mol) at 0° C. over 35 min. The mixture was further kept at 0° C. for 3 hrs. The reaction mass was washed with 5% hydrochloric acid (7.3 g) and 5% aqueous sodium bicarbonate (8.4 g) and then concentrated under reduced pressure with a rotary evaporator to give N-Boc-O-benzenesulfonyl-L-tyrosine methyl ester 5 (4.35 g, yield 100%) as white solid.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=4)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:29]=[CH:30][CH:31]=1)=[O:24]
Reactant: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)OC)c4)cnn23)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (2.8 mg, 0.0040 mmol) was added to a mixture of methyl 3-(3-iodoimidazo[1,2-b]pyridazin-7-yl)benzoate (0.050 g, 0.13 mmol), N-methyl-N′-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (44 mg, 0.16 mmol) and sodium carbonate (28 mg, 0.26 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction vessel containing the mixture was evacuated and refilled with nitrogen 3 times. The reaction was stirred at 100° C. overnight. To this mixture was added aqueous acetonitrile and then filtered, washed with aqueous AcCN, and dried to provide the product. LCMS (M+H)+: m/z=402.1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[CH:19]=1.[CH3:20][N:21]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH2:28][N:21]([CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH3:20])=[CH:30][CH:31]=3)=[O:18])=[CH:11][C:10]=2[CH:19]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccco3)ccc2OCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccco4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 7-(2-furyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.15 g) and triethylamine (0.25 ml) in dimethylformamide (10 ml) was added diethyl cyanophosphate (0.13 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetatehexane to give 7-(2-furyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 148) (0.1 g) as brown crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([Cl:37])[N:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[C:30](=[O:31])[N:29]([O:32][CH3:33])[C:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[N:21]=[CH:22][C:17]=3[CH:16]=2)[CH:9]=1)=[O:6].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CS(C)=O>[Cl:37][C:35]1[CH:34]=[C:4]([CH:3]=[C:2]([N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[N:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[C:30](=[O:31])[N:29]([O:32][CH3:33])[C:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[N:21]=[CH:22][C:17]=3[CH:16]=2)[CH:9]=1)=[O:6]
Reactant: CCNCC
Reactant: COn1c(=O)c(-c2cc(NC(=O)c3cc(Cl)nc(Cl)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Solvent: CS(C)=O
Product: CCN(CC)c1cc(C(=O)Nc2ccc(Cl)c(-c3cc4cnc(NCCN(C)C)nc4n(OC)c3=O)c2)cc(Cl)n1
Temperature: 100 °C

Procedure:
40 mg 2,6-dichloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-isonicotinamide and 50 μl diethylamine were dissolved in 5 ml DMSO and heated at 100° C. in the microwave for 10 min. Addition of further diethylamine and heating in the microwave was repeated multiple times until the reaction was complete. The reaction mixture was purified on HPLC-MS in MeCN/water (1% formic acid) to yield 23 mg.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[ClH:12].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:22][CH2:23][CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1ccc(OCCCCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCOc2ccc(OC)cc2Cl)CC1
Product: Cl
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 3.16 parts of ethyl 1-piperazinecarboxylate, 4.7 parts of 2-chloro-1-(3-chloropropoxy)-4-methoxybenzene, 3.2 parts of sodium carbonate and 67.5 parts of N,N-dimethylformamide was stirred overnight at reflux temperature. After cooling, the reaction mixture was poured into water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2,2'-oxybispropane. The salt was filtered off and dried, yielding 4 parts (50%) of ethyl 4-[3-(2-chloro-4-methoxyphenoxy)propyl]-1-piperazinecarboxylate monohydrochloride (int. 12).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[CH:19](O)[CH2:20]CC2C=CC=CC=2)[CH2:14][CH2:13]1.[C:31]1(CCC(O)=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C=CC=CC=1[C@@H](CC)C(O)=O>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[CH2:19][CH2:20][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)C(O)CCc2ccccc2)CC1
Reactant: O=C(O)CCc1ccccc1
Agent: CC[C@@H](C(=O)O)c1ccccc1O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)CCc2ccccc2)CC1

Procedure:
Compound 12 was prepared in the manner of compound 7 substituting 3-phenylpropanoic acid for (R)-2-hydroxy-phenylbutyric acid in part C to afford compound 12: Mass spectrum (M+1)=380.40.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: CCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 60.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using butyl iodide (1.8 ml; 15.4 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) the alkylated acetamide (0.94 g; 2.93 mmol) is de-acetylated under reflux conditions in 2-propanol (3 ml) and hydrochloric acid (6 N; 11 ml). Pure 5-amino-1-butyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.64 g) is obtained by flash chromatography on silica gel eluted with CH2Cl2/MeOH (50:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:10][CH2:11][O:12][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 174 (2.22 g, 6.93 mmol) and THF (30 mL).cooled to 0° C. and maintained under a N2 atmosphere was added NaH (0.333 g, 8.32 mmol, 60% in mineral oil). The ice bath was removed and the solution stirred for 30 min then MeI (0.519 mL, 8.32 mmol) was added and the yellow solution stirred overnight. The reaction was diluted with H2O and extracted with Et2O. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (SNAP 50) eluting with hexane/EtOAc (4:1) to afford 0.660 g (28%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-methoxypropylcarbamate (176) as a light yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5])#[N:2].C(OC(OCC)OCC)C.[C:20](OC(=O)C)(=O)C.[CH3:27][NH:28][NH2:29]>[Cl-].[Zn+2].[Cl-]>[NH2:2][C:1]1[N:29]([CH3:20])[N:28]=[CH:27][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)NC(=O)CC#N
Reactant: CC(=O)OC(C)=O
Reactant: CNN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(OCC)OCC
Product: CC(C)NC(=O)c1cnn(C)c1N
Temperature: 120 °C
Reaction time: 48 h

Procedure:
1.0 g (8.0 mmol) of 2-cyano-N-(1-methylethyl)acetamide (prepared according to the procedure of Cheikh et al J. Org. Chem., 1991, 56, 970) was combined with 3.1 mL of triethylorthoformate, 5 mL of acetic anhydride and 0.01 g of anhydrous zinc chloride. The mixture was refluxed for 1 hour. A distillation head was placed on the flask and the reaction was heated at 120° C. for 8 hours. After standing for two days the mixture was heated again for 12 hours at 120° C. for 12 hours. The volatiles were removed with a rotary evaporator. Ethanol was added and the volatiles were again removed with a rotary evaporator. This material was dissolved in 15 mL of ethanol. 0.34 mL (6.4 mmol) of methyl hydrazine was added. The reaction mixture was refluxed for 5 hours and then allowed to stand at room temperature overnight. The solvent was removed with a rotary evaporator. The residue was purified by MPLC (ethyl acetate as eluant) to afford 0.14 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=[CH:5][C:6]=1[NH:15][NH2:16]
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1Cl
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)c(Cl)c1Cl
Yield: 79.4 %

Procedure:
100 g of 2,3,4-trichlorobenzotrifluoride are initially introduced, 200 ml of pyridine are added, followed by 100 g of hydrazine hydrate and the mixture is then heated to the reflux temperature for 12 hours. Thereafter, 90% of the pyridine is distilled off and the remaining residue is stirred into 250 ml of water. The crystalline product is filtered off under suction, washed with a little water and dried. 78 g of 2,3-dichloro-4-trifluoromethyl-phenylhydrazine having a melting point of 79° to 80° C. are obtained.