Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][C:4]([Br:20])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.9 %

Procedure:
25 g (100 mmol) of triphenylamine, 18 g (100 mmol) of N-bromosuccinimide, and 400 mL of ethyl acetate were put into a 1000 mL Erlenmeyer flask, and were stirred for approximately 12 hours at the room temperature in the air to be reacted. After the reaction was completed, the reaction solution was washed twice with a saturated sodium carbonate solution to separate an aqueous layer and an organic layer. Then, the aqueous layer was extracted twice with ethyl acetate, and the extract was combined with the organic layer, and washed with a saturated saline solution. The solution was dried with magnesium sulfate, and then filtration was performed. The filtrate was concentrated, and an obtained solid of 4-bromotriphenylamine was re-crystallized with ethyl acetate and hexane, whereby 22 g of a white powder solid was obtained in the yield of 66% (Synthesis Scheme (i-1)).
Reaction SMILES: [NH:1]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:45]([O:47]C1C=CC=CC=1)=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[C@@H:22]([CH3:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].O.OO.Cl>CC(C)=O.CO.CC(O)=O>[CH2:57]([O:56][C:54]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:45]([OH:47])=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[O:30])[C@@H:22]([CH3:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:55])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Agent: Cl
Agent: OO
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C

Procedure:
Z-Ile-Thr(tBu)-Thr(tBu)-Lys(Boc)-OPh (0.884 g, 1.0 mmol) was dissolved in 25 ml acetone and 4 ml H2O added followed by the addition of 3% H2O2 (1.16 ml, 1.0 mmol) and the solution stirred magnetically. The pH was adjusted to, and maintained at, 10.5 by the addition of 0.1N NaOH(a) after stirring at pH 10.5 for 1.5 h, 0.1N HCl was added until the reaction mixture reached pH 3. The white solid which formed was collected by filtration,(b) washed with H2O (~60 ml) and dried in vacuo to yield 0.781 g (96.6%); mp 174°-176° dec;(c)Rf 0.63 (ChCl3 :CH3OH:AcOH; 80-5-1); [α]D25 +13.66 (c 1, CH3OH). Anal: calc. for C41H69N5O11 (808.0): C, 60.94; H, 8.61; N, 8.67. Found: C, 60.83; H, 8.70; N, 8.93.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[CH:27]>C(NCC)C.C(Cl)Cl.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.[Cu]I>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[C:27][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=3[C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]=12
Reactant: C#Cc1ccccc1Cl
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.6 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 1.5 g (11 mmol) of o-chlorophenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 20 ml of diethylamine. The reaction mixture was diluted with 175 ml of methylene chloride and washed three times with water. After drying and evaporation of the solution the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (99:1). By recrystallization of the evaporated eluate there was obtained 3-[(o-chlorophenyl)ethynyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 259°-261°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:28][CH2:27][CH2:26][S:23]3(=[O:25])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(CCCCl)NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)CCCN1C1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid {1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide (410 mg, 0.88 mmol) in DMF (5 mL) is added NaH (60% dispersion in mineral oil, 71 mg, 1.8 mmol). The reaction is heated to 80° C. for 1 h, diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by reversed phase HPLC eluting with a gradient of 0-80% MeCN in water (+0.1% TFA). The desired fractions are lyophilized, partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated to provide the title compound (LC/MS method 1: ES+ m/z 429.4 [M+H]+, Rt=0.63 min).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[Cl:21].[C:22](=[O:24])=[O:23]>C1COCC1.O>[Cl:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[C:17]([I:20])[C:16]=1[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Clc1ccc(I)cc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(I)ccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.45M solution in hexane, 19.4 mmol, 13.4 ml) was added dropwise to a stirred solution of diisopropylamine (21.4 mmol, 3.0 ml) in THF (90 ml) at 0° C. After 30 minutes, the solution was cooled to −78° C. and a solution of 1,2-dichloro-4-iodobenzene (5.30 g, 19.4 mmol) in TIF (10 ml) was added dropwise. After 10 minutes, solid carbon dioxide was added cautiously and the allowed to warm to room temperature over 16 h. The mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified with dilute aqueous hydrochloric acid and then extracted twice with ethyl acetate. The extracts were dried over sodium sulphate and evaporated to give the title compound as a yellow solid (3.59 g). 300 MHz 1H NMR (d6-DMSO) 11.5 (1H, br.s), 7.82 (1H, d, J 8.4 Hz), 7.44 (1H, d, J 8.4 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>>[CH:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12])[N:16]=[CH:17]2)=[O:25]
Reactant: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: N#Cc1ccc(Cn2ncc3cc(C=O)ccc32)c(C(F)(F)F)c1

Procedure:
4-(5-Formyl-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrile was prepared from 4-bromomethyl-3-trifluoromethyl-benzonitrile and 1H-indazole-5-carbaldehyde following General Procedure A.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:6]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:6]1
Reactant: [H][H]
Reactant: CCCCc1nnc(C(=O)N2CCO[C@@H](CN=[N+]=[N-])C2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)N2CCO[C@@H](CN)C2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 91.3 %

Procedure:
To a stirred solution of ((R)-2-azidomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.799 mmol, 0.39 g) in ethyl acetate (4 mL) was added 10% palladium on carbon (0.1 g, wet), and the resulting reaction mixture was subjected to catalytic hydrogenation using a balloon full of hydrogen for 3 h. The catalyst was filtered through a pad of celite, and the celite pad was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate followed by 10% methanolic solution of ammonia (2 M ammonia in methanol) in ethyl acetate to provide ((S)-2-aminomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.33 g) which was converted into dihydrochloride salt using 4 N HCl in dioxane. LCMS: m/z 452.8 [M+1]. 1H NMR (400 MHz, CD3OD) δ 8.12 and 8.13 (1H, s), 7.46 (2H, dd), 7.12 (2H, d), 4.42-4.66 (2H, m), 3.42-4.16 (5H, m), 2.91-3.25 (5H, m), 1.99 (2H, m), 1.83 (2H, m), 1.3-1.69 (10H, m), 0.85 (3H, t)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][C:10]=2[CH3:23])=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([CH3:23])=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:30][C@H:27]2[CH2:28][CH2:29][C@H:24]([NH2:31])[CH2:25][CH2:26]2)=[N:6][CH:7]=1
Reactant: Cc1ncc(NCC2CCOCC2)nc1-c1cc(F)ncc1Cl
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: Cc1ncc(NCC2CCOCC2)nc1-c1cc(N[C@H]2CC[C@H](N)CC2)ncc1Cl
Temperature: 100 °C

Procedure:
To a scintillation vial containing 6-(5-chloro-2-fluoropyridin-4-yl)-5-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (7 mg, 0.021 mmol) was added DMSO and trans-cyclohexane-1,4-diamine (23.73 mg, 0.208 mmol). The homogenous reaction mixture was capped and heated to 100° C. in an oil bath for 4 hr. The crude solution was purified by reverse phase preparative HPLC to yield trans-N1-(5-chloro-4-(3-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1.1 mg, 2.018 μmol, 9.71% yield), LCMS (m/z): 431.2 (MH+), retention time=0.47 min as a TFA salt after lyophilizing.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=CO[C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=[C:2]([CH:1]=[O:5])[O:3][C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.20 ml (2.3 mmol) of oxalyl chloride was added at -78° C., followed by stirring at room temperature for 15 minutes. To this mixture, a solution of 0.684 g (2.064 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=1/1 to 1/3) to yield the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][CH2:8]3)=[O:6])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Product: O=C(CCCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and 1-(4-phenoxylphenyl)piperazine [DE 2631885] were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Iodobenzoic acid (12.4 g) was dissolved in DMF (100 mL) and potassium carbonate (7.6 g) was added. Benzyl bromide (6.5 mL) was then added dropwise over approximately 10 minutes causing a slight exotherm to 24° C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately 300 mL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.0 g). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give a colourless oil (13.08 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([O:20][CH3:21])=[CH:14][C:13]=1[NH:22][C:23]1[C:24]([NH:33][S:34]([C:37]2[CH:47]=[CH:46][C:40]([C:41]([N:43]([CH3:45])[CH3:44])=O)=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[N:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C1COCC1>[CH3:44][N:43]([CH2:41][C:40]1[CH:39]=[CH:38][C:37]([S:34]([NH:33][C:24]2[C:23]([NH:22][C:13]3[CH:14]=[C:15]([O:20][CH3:21])[CH:16]=[C:17]([O:18][CH3:19])[C:12]=3[O:11][CH2:10][CH2:9][CH2:8][OH:7])=[N:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)(=[O:35])=[O:36])=[CH:47][CH:46]=1)[CH3:45]
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)N(C)C)cc2)c(OCCCO)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN(C)C)cc2)c(OCCCO)c(OC)c1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A total of 4 equivalents of LiAlH4, dissolved in THF, are added to 200 mg of 4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N,N-dimethylbenzamide, dissolved in about 10 ml of THF, at 0° C. (ice bath) in a multinecked flask which has been dried by heating, and the mixture is stirred at RT until the starting material has reacted virtually completely (several hours, HPLC check). The reaction mixture is quenched by addition of 5 ml of methanol. The solution is acidified until everything dissolves, evaporated somewhat and purified by preparative HPLC on silica gel RP18 (acetonitrile, water), giving 75 mg of 4-dimethylaminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide as yellow solid (yield 36%); MS-FAB (M+H+)=568.2; Rf (polar method): 1.85 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:22][NH2:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:23][N:22]=[C:8]2[CH2:9][CH2:10][CH3:11]
Reactant: NN
Reactant: CCCC(=O)c1cc(Br)ccc1F
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: CCCc1n[nH]c2ccc(Br)cc12
Temperature: 65 °C
Yield: 52.3 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)butan-1-one (2.0 g, 8.1 mmol) in THF, anhydrous hydrazine (11 mL) in THF was added and heated at reflux (60-70° C.) for 5-6 hours. Xylene was added to the reaction mixture and heated at reflux for 20-24 hours. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography using 15% ethyl acetate/pet-ether as eluents to afford 5-bromo-3-propyl-1H-indazole (1.02 g, 52.3%) as a solid. 1H NMR (CDCl3): δ 7.9 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 2.9 (t, 2H), 1.8 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH2:40]C)[C:6]([NH:8][C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7].[H-].[Na+].[CH3:50]N(C)C=O.CI>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH3:40])[C:6]([N:8]([CH3:50])[C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2CC)c(OC)c1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Yield: 41 %

Procedure:
To a mixture of diethyl (E)-2-[3-({3-methoxy-4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (20.8 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[Cl:8])=[O:4].[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=[O:21]>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]3[C:14]([O:22][C:20](=[O:21])[C:12]=23)=[O:16])[C:6](=[O:5])[C:7]=1[Cl:8])=[O:4]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: C1COCCO1
Product: O=C1OC(=O)c2c1cccc2N1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
20 g (0.12 mol) of 2,3-dichloromaleic anhydride are added to a solution of 18.1 g (0.1 mol) of 3-aminophthalic acid in 90 ml of dioxane. The reaction mixture is stirred at 20°-30° C., whereupon a clear solution is produced over the course of approx. 30 minutes. The dioxane is then distilled off in vacuo (20 mm Hg) and the oil which remains is warmed to 130° C. After 3 hours, the crystalline mass is cooled to 50° C. and mixed with 100 ml of ethyl acetate. The reaction product is filtered off at 10° C. and dried in vacuo at 80° C. 18.1 g (58% of theory) of crystalline 3-(2',3'-dichloromaleinimidyl)-phthalic anhydride are obtained, melting at 229°-230° C. after recrystallisation from anhydrous acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reaction time: 8 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (10 g, 0.03 mol), ethyl acetate (800 mL) and platinum on carbon catalyst were combined in a Parr bottle and then the mixture was hydrogenated overnight. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide 9.1 g of 1,1-dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a yellow syrup. Analysis: Calculated for C15H21N5O2+0.1 CH3CO2C2H5: %C, 59.25; %H, 7.04; %N, 22.43. Found: %C, 58.96; %H, 6.87; %N, 22.46.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C@H:7]([NH:9]C(=O)OC(C)(C)C)[CH3:8])[O:4][N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([C@H:7]([NH2:9])[CH3:8])[O:4][N:3]=1
Reactant: Cc1noc([C@@H](C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc([C@@H](C)N)n1
Reaction time: 16 h
Yield: 151.9 %

Procedure:
To a solution of tert-butyl [(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (6.0 g, 26.4 mmol) in dioxane (40 mL) was added 4 M hydrochloric acid in dioxane (30 mL). The reaction mixture was stirred for 16 h. The solution was concentrated and dried by vacuum to give hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (5.1 g). 1H NMR (500 MHz, CD3OD): δ 4.90-4.83 (m, 1H); 2.41 (s, 3H); 1.72 (d, J=7.0 Hz, 3H). MS 128.2 (M+1).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:17][C@H:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:18][C@H:16]2[CH2:17][C@@H:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:15]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C([C@H]1C[C@@H](O)C1)N1CCCN(C2CCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutanol (50 mg, 0.19 mmol) in DCM (2 ml) at RT was added triethylamine (77 mg, 0.7 mmol) and toluene-4-sulfonyl chloride (108 mg, 0.57 mmol). The mixture was stirred at RT for 1 h and then at 35° C. for 2 h. After cooling to RT and dilution with DCM the mixture was washed with 1:1 H2O/saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (73 mg, 91%).