Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])=[O:11])([O-:3])=[O:2].[OH:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]([NH:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[O:17]
Reactant: CC(C)(CO)C(=O)O
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CO)C(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(2-nitrobenzenesulfonyl)ethylenediamine, 3-hydroxy-2,2-dimethylpropionic acid, EDCI, HOBt, methylene chloride, and DMF was stirred at ambient temperature for 4 hours to yield 3-hydroxy-2,2-dimethyl-N-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)propanamide. A mixture of this compound, triphenylphosphine, a toluene solution of diethyl azodicarboxylate, and THF was stirred at 0° C. for 15 hours to yield 6,6-dimethyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepan-5-one. A mixture of this compound, 4-methylbenzenethiol, potassium carbonate, and acetonitrile was stirred at ambient temperature for 3 hours to yield 6,6-dimethyl-1,4-diazepan-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:15]1[C:20]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=2)=[CH:19][C:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:17][N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl>CN(C=O)C.O>[NH2:28][C:23]1[N:24]=[C:25]([CH3:27])[N:26]=[C:21]([C:20]2[C:15]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:16][CH:17]=[C:18]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:19]=2)[N:22]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (60 mg, 0.271 mmol) and 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (55 mg, 0.190 mmol) in anhydrous DMF (1 mL) cooled in an ice bath was added solid NaHMDS (210 mg, 1.088 mmol) under nitrogen. The resulting orange mixture was stirred with cooling. After 1.5 h, HCl (5 N, 0.25 mL, 1.25 mmol) was added to the mixture. The resulting mixutre was diluted with water (5 mL) and acidified with HCl, 5 N) to about pH 5. The resulting slurry was filtered and washed with water (3×3 mL). The solid was washed with EtOAc to afford the product as a brown solid. The mother liquid was chromatographed on silica gel (0-5% MeOH in EtOAc) to give additional product. The combined product was about 30 mg (32%). m/z (ESI, positive ion): 491.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.82 (m, 4H) 2.46 (s, 3H) 2.84 (t, J=11.35 Hz, 1H) 3.12 (s, 3H) 3.46 (t, J=10.76 Hz, 2H) 3.97 (d, J=12.13 Hz, 2H) 7.78 (br. s., 1H) 7.92 (br. s., 1H) 8.33 (s, 1H) 8.64 (d, J=3.33 Hz, 2H) 8.72 (s, 1H) 9.64 (br. s., 1H) 12.17 (s, 1H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1C=CC=CC=1.CO>[Br:1][CH:2]([CH3:6])[C:3]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:4]
Reactant: C1COCCN1
Reactant: CC(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CO
Product: CC(Br)C(=O)N1CCOCC1

Procedure:
This compound is prepared by reaction of 2-bromopropionylchloride with morpholine under the experimental conditions of Example 10: b.p. 115°-120° C. (0.1-0.2 mm); Rf=0.52 (C6H6 -MeOH 80:20); IR (neat) νmax: 2860, 1660, 1470, 1440, 1280, 1260, 1125, 1040 cm-1. The product is very irritating to the skin and mucosae.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:26])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]2[N:11]=1)[CH3:2].[S:27]([Cl:31])(=O)(=[O:29])[OH:28].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:31])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:26])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.84 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-hexyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 23A) and 0.98 g (8.4 mmol) of chlorosulphuric acid. This gives 300 mg (78.7%) of sulphonyl chloride which is directly reacted further.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C(#N)C>[CH3:27][C:15]([NH:14][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(N)COc1ccc(C#N)cn1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)COc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL ) at room temperature under nitrogen, was added 6-(2-amino-2-methyl-propoxy)-nicotinonitrile (0.1 g, 0.508 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a white solid. MS (DCI) m/z 352 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.08 (3H, m).
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.ClC([O:23][C:24](Cl)(Cl)Cl)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH2:43])[CH2:36][CH2:35]1>C(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH:43][C:24]([NH:12][C:2]23[CH2:9][CH:8]4[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]4)[CH2:3]2)[CH2:11]3)=[O:23])[CH2:36][CH2:35]1
Reactant: NCCCN1CCN(c2ncccn2)CC1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1CCN(c2ncccn2)CC1)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-adamantanamine hydrochloride (1.25 gm, 0.0067 mol) and triethylamine (2.7 gm, 0.027 mol) in 25 mol of dry methylene chloride under a dry nitrogen atmosphere was added, dropwise, trichloromethyl chloroformate (1.33 gm, 0.0033 mol). The resulting suspension was refluxed for three hours, and then a solution of 3-[4-(2-pyrimidyl)-1-piperazinyl]propylamine (1.44 gm, 0.0067 mol) in 15 ml of dry methylene chloride was added. The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted to 200 ml with methylene chloride, washed with 3% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The title compound (TLC on silica gel using a 30% methanol in ethyl acetate solvent system, Rf=0.39) was isolated by gravity chromatography on silica gel and recrystallized from methylene chloride/hexane (1.76 gm, 60% of theory), mp.=172°-173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[N:5]=1)([O-:3])=[O:2].[OH-:15].[Na+]>S(=O)(=O)(O)O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:14])=[O:15])[N:5]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: N#CCCCCn1ccc([N+](=O)[O-])n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)CCCCn1ccc([N+](=O)[O-])n1

Procedure:
A solution of 5-(3-nitropyrazol-1-yl)valeronitrile (0.2 g.) in concentrated sulphuric acid (1 ml.) was kept at 20° for 19 hours. The mixture was diluted with water (4 ml.), basified to pH 10 with 10.8 N sodium hydroxide and extracted with EtOAc (3×5 ml.). The extracts were dried (MgSO4) and evaporated in vacuo to a white solid which was recrystallised from ethanol to give 5-(3-nitropyrazol-1-yl)valeramide, m.p. 129°-131°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:65])[CH2:59][N:60]2[CH:64]=[CH:63][CH:62]=[N:61]2)=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:65][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:59][N:60]2[CH:64]=[CH:63][CH:62]=[N:61]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(Cn1cccn1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cn2cccn2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
HATU (0.209 g, 0.55 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g, 0.50 mmol), 1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanamine (Intermediate 92) (0.202 g, 0.5 mmol) and N,N-diisopropylethylamine (0.174 mL, 1.00 mmol) in N-methyl-2-pyrrolidinone (3.0 mL) at room temperature under argon. The resulting solution was stirred overnight. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.216 g, 76%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[F:30].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:21][NH:22][S:31]([C:26]2[CH:27]=[CH:28][C:29]([F:30])=[C:24]([Cl:23])[CH:25]=2)(=[O:33])=[O:32])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)c(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (1.0 mL) at room temperature under Ar was added a solution of 3-chloro-4-fluorophenylsulfonyl chloride (0.06 g, 0.26 mmol, 1.1 eq.) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h, diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation yielded the crude 4-[(3-chloro-4-fluoro-benzenesulfonylamino)-methyl]-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.09 g, 0.14 mmol, ˜62%). 1HNMR (300 MHz, CDCl3): δ 8.66 (d, 1H), 7.81-7.73 (m, 3H), 7.34 (m, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 3.79 (m, 2H), 3.13 (m, 3H), 2.19 (m, 3H), 1.77 (m, 2H), 1.56 (s, 9H). MS(ESI): 509 (M−Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12]1([CH2:18][O:19][C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=2[O:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[O:19][CH2:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:29][CH2:28]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: c1ccc(OCC2CCNCC2)c(OCC2CCCCC2)c1
Reactant: COc1ncc(Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ncc(Cl)cc1CN1CCC(COc2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
150 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde and 291 mg of 4-[2-(cyclohexylmethyloxy)phenoxymethyl]piperidine were dissolved in 5 ml of 1,2-dichloroethane. To the mixture were added 0.06 ml of acetic acid and 214 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. An aqueous saturated sodium bicarbonate was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 285 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[N+:32]([O-])=O)[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[NH2:32])[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c([N+](=O)[O-])c2C3=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c(N)c2C3=O)cc1

Procedure:
A suspension of 0.426 g of 1-amino-6-methyl-5-nitro-2-anthraquinonecarboxylic acid p-heptylphenyl ester, 50 ml of toluene, 50 ml of ethanol and 0.10 g of palladium/barium carbonate catalyst poisoned with 2 wt.% lead was hydrogenated at room temperature until the hydrogen uptake came to a standstill. The mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel with methylene chloride as the eluent. Recrystallization from methylene chloride/hexane, yielded 0.334 of 1,5-diamino-6-methyl-2-anthraquinonecarboxylic acid p-heptylphenyl ester as violet crystals; m.p. (C-N) 163.7°-165.7° C., cl.p. (N-I) 190.9°-191.4° C., nematic; E277 =15280, E524 =14700.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=2)[CH2:28][N:29]([CH3:41])[C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[ClH:18].[Cl:1][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:44]=[CH:43][CH:42]=[C:27]([CH2:28][N:29]([C:30](=[O:40])[CH2:31][NH2:32])[CH3:41])[CH:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1Cl
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1)C(=O)CN
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3 chloro-4-(piperazin-1-yl)benzoic acid hydrochloride (142 mg) was suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (190 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino)methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (72 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([NH2:22])[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OCCNC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCNC(=O)Nc1cc(N)cc(N)c1
Temperature: 17 °C
Reaction time: 1 h

Procedure:
8.3 g of 5% palladium carbon, 83.0 g (0.244 mol) of 2-(3,5-dinitrophenylureido)ethyl isobutyrate (compound 12) and 800 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was raised to 5 kg/cm2. The autoclave contents were stirred at room temperature (17° C.). Ten minutes later, the autoclave inside temperature rose to 43° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Ten minutes later, the temperature became 58° C. and the pressure dropped to 1 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (4.5 kg/cm2), stirring was continued for 60 minutes (the temperature dropped to 26° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from 300 ml of butanol to obtain 2-(3,5-diaminophenylureido)ethyl isobutyrate (compound 13). Yield: 55.0 g (81%) Melting point: 89-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.ClCCl.C(OC(C)C)(C)C>N1C=CC=CC=1>[CH3:11][C:8]1([CH3:10])[CH2:7][C:6]2[C:12]([CH3:13])=[C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]=2[O:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C)c(C)c3c(c2C)CC(C)(C)O3)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
5-Amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 2.00 g, 9.74 mmol) and p-toluenesulfonyl chloride (2.04 g, 10.7 mmol) were dissolved in pyridine (30 ml) and stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with 1N hydrochloric acid and saturated saline and dried and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate, 97:3). The crude crystals were recrystallized from dichloromethane-isopropyl ether to obtain the desired compound (2.41 g, yield: 68.8% yield), m.p. 219°-220° C. (dichloromethane-isopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)nn1-c1ccccc1
Yield: 69.5 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (85 μL, 0.97 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (223 mg, 70%) was obtained as a white powder.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15]OC)[O:12][C:9]2=[N:10][CH:11]=1)=O)C.O1[C:22]2=[N:23][CH:24]=C(CCCNC)C=[C:21]2C=C1>>[CH3:24][NH:23][CH2:22][CH2:21][CH2:4][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH3:15])[O:12][C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)c1cnc2oc(COC)cc2c1
Reactant: CNCCCc1cnc2occc2c1
Product: CNCCCc1cnc2oc(C)cc2c1

Procedure:
Prepared from 2-methoxymethyl-furo[2,3-b]pyridine-5-carboxylic acid ethyl ester in analogy to the methods described for (3-furo[2,3-b]pyridin-5-yl-propyl)methyl-amine.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:14]=2)[C:9](=[NH:13])OCC)[CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.Cl.Cl.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:36]2[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:37]2)=[N:33][C:34]=1N>C(O)C>[CH:1]1([C:4]2[CH:14]=[C:8]([C:9]3[NH:13][C:34]4=[N:33][C:32]([N:36]5[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([N:44]6[CH2:48][CH2:47][CH2:46][CH2:45]6)=[O:43])[CH2:37]5)=[CH:31][CH:30]=[C:29]4[N:28]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)c1cncc(C2CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cncc(C5CC5)c4)[nH]c3n2)C1)N1CCCC1
Yield: 5.8 %

Procedure:
To a solution of ethyl 5-cyclopropylnicotinimidate (0.2 g, 1.04 mmol) in ethanol was added acetic acid (0.1 mL), triethylamine (0.1 mL) and a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride salt (0.4 g, 1.1 mmol) in ethanol. The reaction mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure and to the resulting residue was added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (0.025 g). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (br s, 2H), 1.07 (d, 2H), 1.47-1.74 (m, 4H), 1.74-1.96 (m, 5H), 1.98-2.10 (m, 1H), 2.61 (br s, 2H), 2.92 (d, 2H), 3.41-3.59 (m, 2H), 4.33 (d, 1H), 4.39 (d, 1H), 6.86 (d, 1H), 7.81 (d, 1H), 8.00 (br s, 1H), 8.47 (br s, 1H), 9.05 (br s, 1H), 13.07 (br s, 1H). MS (ES+) (M+H) 417.36; LCMS retention time 3.03 min (Method S).