Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][C:19]=12.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C=O.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])=[N:20][C:19]=12
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reaction time: 18 h
Yield: 102.1 %

Procedure:
Triethylamine (5.6 ml, 40 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5(4H)-one (5.47 g, 19.5 mmol) and p-toluenesulfonyl chloride (3.82 g, 20 mmol) in dry N,N-dimethylformamide (100 ml) at room temperature under nitrogen. The brown suspension was stirred for 18 h then diluted with water (800 ml). The yellow precipitate was collected, washed sequentially with water and diethyl ether, then dried in vacuo to give 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (8.65 g, 100%). δH (400 MHz; CDCl3) 2.42 (3H, s), 7.23 (2H, d, J=8), 7.28-7.34 (2H, m), 7.47-7.50 (1H, m), 7.76 (1H, dd, J=8 and 8), 7.87 (1H, ddd, J=7, 7 and 2), 8.04-8.08 (3H, m), 8.30 (1H, dd, J=8 and 1), 8.70 (1H, d, J=8); m/z (ES+) 435 (M+H+).
Reaction SMILES: OC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP([O:38][C@H:39]3[O:44][C@H:43]([C:45]([O-:47])=[O:46])[C@@H:42]([OH:48])[C@H:41]([OH:49])[C@H:40]3[OH:50])([O-])=O)([O-])=O)[C@@H](O)[C@H]2O)C=1.[Na+].[Na+].[Na+].CC(N[C@H]1[C@@H](OP(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)O[C@H](CO)[C@H](O)[C@@H]1O)=O>>[OH:38][CH:39]1[O:44][C@H:43]([C:45](=[O:46])[OH:47])[C@@H:42]([OH:48])[C@H:41]([OH:49])[C@H:40]1[OH:50]
Reactant: O=C([O-])[C@H]1O[C@H](OP(=O)([O-])OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: [Na+]
Product: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Saccharide chain fractions were prepared in the same manner as that of (A) except that UDP-GlcA was added again instead of UDP-GalNAc to prepare sample solutions for MS.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([CH:24]1[CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH:25]1[C:33](O)=[O:34])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:22]([CH:24]1[CH2:32][C:27]2([O:28][CH2:29][CH2:30][O:31]2)[CH2:26][CH:25]1[C:33]([NH:2][NH:1][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:6]2=[N:7][CH:8]=1)=[O:34])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CCC1CC2(CC1C(=O)O)OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC2(CC1C(=O)NNc1cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A 50 mL round bottom flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol, Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6 mmol) and the resulting yellow suspension was stirred at rt for about 3 h. To the reaction solution was added DCM (25 mL) and the solution was washed with water and brine (20 mL each). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown oil. The crude product was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM over 25 min. to give 8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide as a foam (0.50 g, 89%): LC/MS (Table 1, Method c) Rt=1.49 min; MS m/z: 486 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[F:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: O=C(Cl)CF
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CF)c1ccc(F)cc1F
Yield: 36 %

Procedure:
1,3-Difluorobenzene (2.02 g; 17.7 mM) and anhydrous aluminium chloride (2.60 g; 19.47 mM) were stirred together under dry nitrogen at room temperature. A solution of fluoroacetyl chloride (1,71 g; 17.7 mM) in anhydrous methylene chloride (2 ml) was added over 30 minutes. The mixture was then warmed at about 50° for 3 hours. On cooling methylene chloride (40 ml) was added and the mixture was poured onto ice. The methylene chloride layer was separated, dried over magnesium sulphate and evaporated to give a white solid. This material was chromatographed on a column of silica eluting with a mixture of hexane/methylene chloride (65:35 by volume). The product-containing fractions were collected. The title compound crystallised on evaporation of these fractions and was dried in a vacuum desiccator to a colourless crystalline solid (1.12 g; 36% yield), melting point 57°-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C@@H:4]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])[CH2:5][N+:6]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.Cl>O1CCCC1.O1CCCC1.O>[ClH:1].[NH2:6][CH2:5][C@H:4]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[OH:15])[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1]
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccccc1Cl)[C@H]1CCCC[C@H]1O
Reaction time: 15 h

Procedure:
A solution of 56.3 g (0.2 mol) of rac-(2S*)-2-[(R*)-2-chloro-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise while stirring to a suspension of 18.9 g (0.5 mol) of lithium aluminium hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 50°. The reaction mixture is then stirred at 50° for a further 15 hours. After cooling the mixture is treated first with 50 ml of ethanol and subsequently with tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The oily residue obtained is treated with 3N hydrochloric acid, whereupon the mixture is extracted twice with 250 ml of ether each time. The aqueous phase is made alkaline with 3N sodium hydroxide solution and extracted twice with 500 ml of methylene chloride each time. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The crude product is obtained in the form of a yellow oil; it is converted into the hydrochloride in the usual manner. After repeated recrystallization from methylene chloride/methanol there is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-2-chlorobenzyl]cyclohexanol hydrochloride of m.p. 278°-280°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCn1nc2c(N)nc3c(c2c1CCCCN)CCCC3
Reaction time: 24 h

Procedure:
A solution of 1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (2.40 g, 8.06 mmol) in trifluoroacetic acid (20 mL) was treated with platinum (IV) oxide. The mixture was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) for 1 day, and then was diluted with chloroform (50 mL) and methanol (25 mL). The mixture was filtered through CELITE filter agent. The filtrate was concentrated under reduced pressure to yield 6.0 g the bis-trifluoroacetic acid salt of 1-(4-aminobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine in residual trifluoroacetic acid as a yellow liquid.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([N:33]([CH3:45])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH3:44])[S:40](=[O:43])(=[O:42])[NH2:41])=[O:32])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO.C1COCC1>[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([N:33]([CH3:45])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH3:44])[S:40](=[O:42])(=[O:43])[NH2:41])=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)N(C)CCOCCN(C)S(N)(=O)=O)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Reaction time: 5 h
Yield: 83 %

Procedure:
A solution of NaOH (1.00 g, 25 mmol) in water (5 mL) was added to a stirred solution of intermediate 7 (370 mg, 0.602 mmol) in MeOH (30 mL) and THF (10 mL). After 5 h, the solution was concentrated under vacuum. The pH was then adjusted to 5 with acetic acid (AcOH). Then, the reaction mixture was extracted with AcOEt, the organic layer dried over anhydrous Na2SO4, filtered and the filtrate evaporated to yield 300 mg (83%) of 3-cyclohexyl-1-methyl-2-(2-{2-[methyl(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)amino]-2-oxoethoxy}phenyl)-1H-indole-6-carboxylic acid 8 as a white powder: m/z=601 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]([N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]1[CH2:36][O:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:1].[ClH:1].[C:16]1([C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 98 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(benzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (89.5 mg, 0.175 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 63.8 mg (98%) of the desired product as a white solid. LC-MS: RT=3.05 min, [M+H]+=298.1.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11]
Reactant: COc1ccc(C(C#Cc2ccccc2)CNC(=O)CNC(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C#Cc2ccccc2)CNC(=O)CN)cc1OC1CCCC1
Reaction time: 1 h

Procedure:
A solution of 4-t-butoxycarbonylaminomethylcarbonylamino-3-(3-cyclopentyloxy-4methoxyphenyl)-1-phenyl-1-butyne (290 mg, 0.59 mmol) in CH2Cl2 (5 ml) at 0° was treated with trifluoroacetic acid (4 ml). After 1 hr, all the solvents were evaporated. The residue was partitioned between H2O and Et2O, basified with aqueous NaOH, and the Et2O layer seperated, dried, and the solvent evaporated, and gave 4-aminomethylcarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne, 200 mg (86%). The salt was formed by treating this amine (180 mg) in Me2CO (2 ml) with sulfamic acid (82 mg). The solution was concentrated to almost dryness, and the resultant crystals were triturated with Me2CO, and gave the titled compound, mp 119-124°. 1H NMR (400 MHz, CDCl3) δ 8.22 (t, 1 H), 7.44 (m, 3 H), 7.28 (m, 3 H), 7.02 (d, 1 H), 6.94 (m, 1 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.04 (t, 1 H), 3.80 (s, 3 H), 3.76 (m, 2 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.18 (m, 1 H), 2.04 (m, 2 H), 1.80-1.98 (m, 6 H), 1.52-1.72 (m, 4 H), 1.08-1.32 (m, 6 H).
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:19][CH3:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:9])[C:4](=[O:21])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:21])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([O:19][CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: CON(Cc1ccccc1C)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccccc1C)OC
Yield: 61 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(2-methylbenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (61% yield); mp 80–82° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.39 (3H, s, CH3), 3.62 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.5 (1H, s, CH), 7.22–7.28 (4H, m, aromatics), 13.5 (1H, broad s, OH). Anal. calcd for C14H17NO5: C, 60.20; H, 6.13; N, 5.01. Found: C, 60.07; H, 5.88; N, 4.84.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](OC)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC(C[AlH]CC(C)C)C>O1CCCC1>[OH:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1
Reactant: COC(=O)c1ccc2occc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc2occc2c1

Procedure:
5.8 g (32.9 mmol) of methyl benzofuran-5-carboxylate are stirred analogously to Example 1 g in 50 ml of tetrahydrofuran with 64.5 ml (98.6 mmol) of DIBAL (1.53 molar) at -70° C. overnight.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[NH2:17][C:18]([NH2:20])=[O:19].Cl.CO>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:17][C:18]([OH:19])=[N:20][CH:5]=1)([O-:15])=[O:14]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Temperature: 70 °C
Yield: 17.7 %

Procedure:
A solution of 3-(dimethylamino)-2-(2-nitrophenyl)acrylaldehyde (2.00 g, 9.08 mmol), urea (0.60 g, 9.99 mmol) and concentrated hydrochloric acid (0.50 ml) in ethanol (25 ml) was heated at 60° C. for 18 hours under a nitrogen atmosphere. An additional aliquot of concentrated hydrochloric acid (0.50 ml) was added followed by heating at 70° C. for 24 hours. The solvent was removed by evaporation under reduced pressure. The residue was crystallised from methanol yielding the title compound (0.35 g, 18% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=3)[NH2:15])=[CH:8][C:6]=2[N:7]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.Cl[C:42]([O:44][CH2:45][Cl:46])=[O:43]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([NH:15][C:42](=[O:43])[O:44][CH2:45][Cl:46])[CH:16]=[CH:17][CH:18]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: O=C(Cl)OCCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1)OCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a 100 mL round bottom flask, 3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline (1.0 g, 0.0029 mol), 1,8-bis(dimethylamino)naphthalene (0.626 g, 0.0029 mol) and chloroform (60 mL) were added. The reaction mixture was cooled in an ice bath. To the same flask was added chloromethyl chloroformate (0.377 g, 0.0029 mol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform, washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide the title compound as a yellow solid (1.25 g, 98.4%). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (br s, 1H), 9.07 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.94 (br s, 1H), 7.62-7.51 (m, 3H), 6.01 (s, 2H), 4.98-3.98 (br s, 4H), 3.81 (t, J=4.4 Hz, 4H). LC-MS (ESI): Calculated mass: 433.07; Observed mass [M+H]+: 433.8 (RT: 1.63 min).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:32])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:32])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 37.4 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.500 g), KOH (0.200 g), water (5 mL) and THF (10.0 mL) to afford 0.150 g of desired product.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[C:8]([CH3:18])[CH:7]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:16]([O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:22]2[CH:23]=[CH:24][C:25]3[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)=[CH:39][CH:38]=4)=[O:35])=[CH:27][C:26]=3[CH:52]=2)=[CH:7][C:8]=1[CH3:18])[CH3:17]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
In toluene (10 ml), ethanol (1 ml) and water (1 ml) were suspended 4-(2-ethoxyethoxy)-3-methylphenyl borate (119 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (212 mg) and potassium carbonate (147 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was stirred under argon atmosphere at 100° C. for 8 hours and cooled. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate (twice). The organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol=7:1) and recrystallized from ethanol (22.5 ml) to give colorless crystals of 7-[4-(2-ethoxyethoxy)-3-methyl-phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 129) (131 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:22])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].S(Br)([Br:25])=O>O>[Br:25][CH2:22][CH:10]([CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C(CCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Product: CCOC(=O)COCCC(CBr)C(O)C(NC=O)C(=O)OCC
Reaction time: 0.17 h

Procedure:
7.5 g (23.6 mmol)of ethyl 6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-hexanoate are dissolved in 75 ml of CH2C12 and 2.2 ml (28.3 mmol) of thionyl bromide are then added dropwise at room temperature to this solution. After 1 hour 50 ml of water are added and the reaction mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and once with brine. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving ethyl 4-bromomethyl-6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-hexanoate as a yellow oil which is further reacted without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(/N=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 98.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in 42 mL of ethonal was added methyl 4-aminobenzoate (4.07 g, 27 mmol), and the reaction mixture was stirred over weekend. The yellow precipitates were filtered, and 8.47 g of (E)-methyl 4-(4-chloro-3-nitrobenzylidenamino)benzoate a yellow solid was obtained. (Yield=98%). (E)-methyl 4-(4-chloro-3-nitrobenzylideneamino)benzoate (8.47 g, 26.6 mmol) and yttrium(III) trifluoromethanesulfonate (800 mg, 1.33 mmol) was dissolved in dry tetrahydrofuran (100 mL), and then cooled below 0° C. Isobutyl aldehyde (2.30 g, 31.9 mmol) was added below 0° C. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed most of starting material was consumed. 50 mL of ethyl acetate and 50 mL of water were added to the mixture, and the separated organic layer was washed with brine again. The organic layer was dried over sodium sulfate and purified on silica gel to afford 4.9 g of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield=47%). MS (ESI+APCI) M+1=373.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:10]=[CH:11][C:12](O)=[O:13]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9](/[CH:10]=[CH:11]/[C:12]([Cl:3])=[O:13])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: COc1ccc(/C=C/C(=O)Cl)cc1OC

Procedure:
To 5 mL of dried thionyl chloride (SOCl2) contained in a reaction vessel was slowly added 4 g (19 mmol) of 3,4-dimethoxy cinnamic acid (140) and 50 μl of dried N′N′-dimethylformamide. The contents of the reaction vessel were mixed continuously at room temperature for 10-15 minutes, and the resulting product was dried in vacuo at 30-40° C. to yield (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride (180).