Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]C)[CH:7]=1)=[O:5]>Br>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[O:5]
Reactant: COc1cccc(C(=O)c2ccccc2N)c1
Agent: Br
Product: Nc1ccccc1C(=O)c1cccc(O)c1
Yield: 92.7 %

Procedure:
2-Amino-3'-methoxybenzophenone (6.92 g, 30.5 mmol) was dissolved in 125 mL of 48% hydrobromic acid and the solution was heated at refluxed for 12 h. The solvent was removed by rotary evaporation and the resulting red solid was distributed between saturated sodium bicarbonate (400 mL) and CH2Cl2 (500 mL). The aqueous layer was washed with CH2Cl2 (2×100 mL) and the combined organic layers were dried with sodium sulfate and concentrated in vacuo to afford 6.03 g (92% yield) of 2-amino-3'-hydroxybenzophenone as a red oil. Recrystalization from ethyl acetate/hexanes (reflux, 4° C.) provided light red crystals: mp 130-132° C., Rf 0.25 (75:25, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 5.25 (b, 1), 6.06 (b, 2), 6.58 (dt, 1, J=1.0, 7.5), 6.72 (d, 1, J=8.2), 6.98 (dd, 1, J=2.2, 8.2), 7.07 (t, 1, J=2.0), 7.15 (d, 1, J=7.5), 7.28 (m, 2), 7.45 (dd, 1, J=1.5, 8.0). 13C NMR (101 MHz): δ 77.2, 115.6, 115.7, 117.0, 118.2, 121.7, 129.4, 134.4, 134.6, 141.6, 150.9, 155.4. HRMS (FAB, m-nitrobenzyl alcohol) calcd for C13H11NO2 (M+H) 214.0843, found 214.0867.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][O:38][CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:39][O:38][NH:37][S:34]([C:30]1[CH:31]=[C:32]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:28][CH:29]=1)(=[O:36])=[O:35]
Reactant: CONS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: CONS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)c2)c1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.20 g, 0.56 mmol) and 3-bromo-N-methoxy-benzenesulfonamide (example H.3) (0.149 g, 0.56 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 43%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:36]I>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][I:36]
Reactant: II
Reactant: COC(=O)CCCC#CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCC#CCI
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
A solution of (30) (1.347 g, 8.6 mmol) in 5 mL dichloromethane was added to a mixture of triphenylphosphine (2.725 g, 10.4 mmol), imidazole (726 mg, 10.7 mmol), and iodine (2.602 g, 10.3 mmol) in 34 mL dichloromethane, rinsing with 5 mL dichloromethane. After 40 minutes, the dichloromethane was evaporated in vacuo to about 2 mL and the resulting mixture filtered through basic alumina, washing with 10% ethyl acetate/hexanes. Purification by flash chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.878 g (7.1 mmol, 83%) of the propargyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl.CCOCC>[C:2]1([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aniline (1.86 g, 0.02 mol) was dissolved in methylene chloride under nitrogen and triethylamine (3.8 mL, 0.02 mol) was added. This solution wascooled in an ice bath and a solution of p-toluenesulfonyl chloride (3.8 g, 0.02 mol) was added dropwise via a syringe. After stirring this solution for 4 h at room temperature, TLC analysis (silica gel, 20% ethyl acetate/hexane) indicated completion of the reaction. The reaction mixturewas poured into ether and the precipitate filtered. The ether layer was washed with water, dried over MgSO4 and concentrated to yield an oilymaterial. This crude product was chromatographed on silica using 35% ethyl acetate and hexane to obtain a solid which was further recrystallized in methylene chloride/hexane; m.p. 104° C.; 1H NMR (CDCl3) δ2.36 (s, 3H), 7.07-7.25 (m, 8H), 7.67-7.69 (d, 2H).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[H][H].Cl>[Pd]>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: O=C1OC(Cl)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: O=C1OCc2ccccc21

Procedure:
824.5 weight parts of 3-chlorophthalide were melted at 85° C. in an autoclave, 25.3 parts of catalyst (5% Pd on BaSo4), and a hydrogen stream of 180 l/h was introduced with vigorous agitation. The excess hydrogen and the hydrogen chloride that evolved were removed as in the above examples. After 81/2 hours, the evolution of hydrogen chloride ceased. The melt was separated from the catalyst. In the distillation that followed, 608 weight-parts of phthalide were obtained (90.7% of the theory) having a content of 99.6% phthalide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18](=[O:19])([O:20][CH2:21][CH3:22])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2,4-difluorophenol (2 g, 15.4 mmol) in CH2Cl2 (20 mL) was added triethyl amine (3.21 ml, 23 mmol) and ethyl chloroformate (1.77 ml, 18.4 mmol) at 0° C. After stirring the mixture for 1 h at RT, sat. NaHCO3 solution (30 mL) was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (1×25 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 2,4-difluorophenyl ethyl carbonate (3.11 g, 100% yield) as a liquid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>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>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1F], 1-iodo-3-trifluoromethyl-benzene, was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to yield the title compound as brown oil.
Reaction SMILES: C(NC1CC2C(=CC=CC=2)C1)(=O)C.ClS(O)(=O)=O.C([NH:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:29]=2)[CH2:24]1)(=O)C.N>C1COCC1.O>[S:32]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([NH2:22])[CH2:31]2)(=[O:34])(=[O:35])[NH2:33]
Reactant: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1
Agent: CC(=O)NC1Cc2ccccc2C1
Agent: N
Agent: O=S(=O)(O)Cl
Solvent: C1CCOC1
Solvent: O
Product: NC1Cc2ccc(S(N)(=O)=O)cc2C1
Temperature: 25 °C

Procedure:
1.75 g. of N-acetyl-2-indanamine (0.01 mole) was added to 20 g. of chlorosulfonic acid (0.18 mole), stirred at -60° C. and allowed to warm to 25° C. The mixture was stirred until the reaction was complete, poured into cold water and extracted with ethyl acetate. Evaporation gave the crude N-acetyl-5-chlorosulfonyl-2-indanamine which was converted to N-acetyl-5-sulfamyl-2-indanamine with ammonia in THF. The N-acetyl sulfonamide was purified by recrystallization from water, m.p. 237°-239° C. and hydrolyzed in refluxing 10% hydrochloric acid to give 5-sulfamyl-2-indanamine which was recrystallized from methanol-ether, m.p. 261°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:7]=1.[CH3:17][NH2:18].C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:8]([NH:18][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CN
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(c1ccccc1)c1cc(Br)ccc1O

Procedure:
(5-Bromo-2-hydroxy-phenyl)-phenyl-methanone (1.00 g, 3.536 mmol), 4 Å molecular sieves (1 g), and DCM are mixed then methylamine in THF (8.84 mL, 2M, 17.682 mmol) is added to followed by p-toluenesulfonic acid in acetic acid (0.474 mL, 12%, 0.354 mmol). Sodium triacetoxyborohydride (4.20 g, 19.80 mmol) is added in three separate portions. The mixture is quenched with saturated Na2CO3 solution and extracted with EtOAc. The organic phase is dried over Na2SO4 and the solvent removed on a rotary evaporator. This provides the desired compound which is used in the next step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].O[N:9]=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]([CH3:23])=[CH:12][C:11]1=2.[I-].[Na+]>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[C:1]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:23])[N:14]2[CH2:19][C:20]([OH:22])=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(n1CC(=O)O)CCCC2=NO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1cccc2c1cc(C)n2CC(=O)O
Temperature: 95 °C
Reaction time: 1.25 h

Procedure:
Acetic anhydride (1.0 mL, 10.6 mmol) was added to a stirred slurry of 2-[4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetic acid (2.0 g, 9.0 mmol) in a mixture of acetic acid (10 mL) and xylene (10 mL) at r.t. in reaction flask 1 (mildly exothermic addition) then the mixture was held with stirring for 75 mins. Meanwhile, reaction flask 2 was charged with acetic acid (5 mL), xylene (5 mL), acetic anhydride (2.6 mL, 27.5 mmol), and sodium iodide (270 mg, 1.80 mmol) and the mixture was heated to 90-100° C. with stirring. The contents of reaction flask 1 were transferred to reaction flask 2 in aliquots over a period of 1.5 h, whilst maintaining the reaction temperature at 90-100° C. Reaction flask 1 was rinsed with a mixture of xylene (2 mL) and acetic acid (2 mL) which was transferred into reaction flask 2. Subsequently, the reaction mixture was maintained at 100° C. for a further 2.5 h and was then allowed to cool to r.t. The liquid phase was decanted off from a thick residue in the reaction flask and the residue was washed with acetic acid (5 mL) followed by xylene (5 mL). The decanted liquid and washes were combined and evaporated to dryness in vacuo to leave a dark brown residue. Analysis by HPLC and LC-MS showed 29.2 area % of a peak giving m/z 247 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19]O)[O:7][CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>N1C=CC=CC=1>[Cl:41][CH2:19][C@H:8]1[O:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]1[O:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)OC[C@@H]1OC(C)=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CCl)OC[C@@H]1OC(C)=O
Yield: 59 %

Procedure:
895 mg (3.08 mmol) of 1,5-anhydro-2,3,4-tri-O-acetyl-D-glucitol was dissolved in 30 ml of pyridine, and 1.95 g (7.4 mmol) of triphenylphosphine and 10 ml of carbon tetrachloride were added. The mixture was allowed to react at 45° to 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (80 ml). The chloroform layer was washed with 1N aqueous hydrochloric acid solution (80 ml) and water (80 ml), dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 40 g) and eluted with chloroform-methanol (300:1). The eluate was crystallized from ethyl acetate-hexane to obtain 562 mg (1.82 mmol, 59%) of 1,5-anhydro-6-chloro-6-deoxy-2,3,4-tri-O-acetyl-D-glucitol as a colorless needle crystal. Shown below are physicochemical properties of the crystalline compound thus obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][C:57]1[CH:62]=[CH:61][N:60]=[CH:59][C:58]=1[C:63](O)=[O:64].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:63]([C:58]1[CH:59]=[N:60][CH:61]=[CH:62][C:57]=1[CH3:56])=[O:64]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccncc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Yield: 48.4 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 4-methyl-3-pyridinecarboxylic acid (44.5 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was reduced in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with aqueous NaHCO3 (5 ml), twice. The organic layer was dried with dried magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo. The residue was then dissolved in diethyl ether (50 ml) and transferred to a 100 ml round bottom flask and reduced to dryness in vacuo to yield the title compound (67 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: CC(Cl)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccccn1)n1ncc2ncc(Br)cc21
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To an ice-cooled solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (0.60 g, 3.0 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 488 mg, 12.2 mmol). After 30 min, 2-(1-chloroethyl)pyridine (1.73 g, 12.2 mmol) was added to reaction mixture, and the resulting suspension was warmed to 27° C. After 17 h, the reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (3×30 mL). The organic extracts were concentrated in vacuo. Purification by flash column chromatography (6→15% ethyl acetate in petroleum ether) afforded 6-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridine (450 mg, 49% yield). LRMS (ESI): [MH]+=304.6.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.O=P(Cl)(Cl)Cl.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=3)=[O:33])=[C:18]([CH:29]([CH3:31])[CH3:30])[N:19]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][C:14]=1[F:44]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:22]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([F:44])=[C:13]([NH:12][C:2]3[CH2:3][CH2:4][CH2:5][N:1]=3)[CH:21]=2)[C:17]([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=2)=[O:33])=[C:18]1[CH:29]([CH3:30])[CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCC3)cc2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 2-pyrrolidinone (47 mg, 0.55 mmol) and POCl3 (0.10 ml, 1.1 mmol) was stirred at 0° C. to room temperature for 2h. To the above mixture was then added a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 50 mg, 0.11 mmol) in toluene (3 ml). The reaction was heated to 110° C. for 16 h and was cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase chromatography on C18 bonded silica gel (MeOH) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=3)[CH2:19][CH2:20][CH3:21])[C:13]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: OB(O)c1ccc(F)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(F)cc2)c1C

Procedure:
Prepared from 4-fluorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:10])=[C:5](Cl)[C:3]=1[NH2:4].Cl.S(=O)(=O)(O)O>[Pd].[Ta].C(Cl)Cl>[Cl:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([Cl:10])[CH:7]=1)[NH2:4]
Reactant: Nc1c(Cl)c(Cl)cc(Cl)c1Cl
Agent: [Pd]
Agent: [Ta]
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 88.9 %

Procedure:
57.7 g (0.25 mol) of 2,3,5,6-tetrachloroaniline, 250 ml of 36% strength aqueous solution of hydrochloric acid, 5 ml of concentrated sulphuric acid and 5 g of a 5% strength palladium/active charcoal catalyst are introduced into an 0.7 l autoclave made of tantalum. The autoclave is flushed first with nitrogen and then with hydrogen. The dechlorination is carried out over the course of 2 hours at 250° C and a hydrogen pressure of 200 atmospheres gauge. After the reaction, the catalyst is filtered off and washed twice with hot water. The reaction solution together with the wash water is rendered alkaline and warmed. After cooling, the reaction product is extracted twice with 150 ml of methylene chloride. After distilling off the methylene chloride, and subsequent fractional distillation, 36 g of 3,5-dichloroaniline (yield: 89% of theory) are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[CH3:20][C:21]1[CH:30]=[C:29]([NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[H-].[Na+]>>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[S:11][C:10]4[N:12]=[CH:13][CH:14]=[N:15][C:9]=4[N:8]([CH2:16][O:17][CH3:18])[C:7]=3[CH:19]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: Cc1cc(N)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Product: COCN1c2cc(CNc3cc(C)nc4ccccc34)ccc2Sc2nccnc21
Yield: 95.1 %

Procedure:
Similar to Example 1094, 307 mg of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was treated with 354 mg of 2-methyl-4-aminoquinoline in the presence of 91 mg of sodium hydride (60% oily) to thereby give 413 mg of 8-[(2-methylquinolin-4-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine as a yellow oily substance. Then this product was deblocked by the same method as the one of Example 9 to thereby give 114 mg of the title compound as, yellow crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:44]=[N:43][C:34]2[NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][C:37]1([CH3:41])[C:36](=[O:42])[NH:35][C:34]2[N:43]=[CH:44][C:31](/[CH:12]=[CH:11]/[C:10]([N:9]([CH2:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=3[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:14])=[O:13])=[CH:32][C:33]=2[CH2:39][NH:38]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)c1OCC(C)C
Yield: 36.7 %

Procedure:
A solution of N-(2-isobutoxy-3-methoxybenzyl)-N-methylacrylamide (0.407 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.11 mmol) and P(o-tol)3 (0.067 g, 0.22 mmol) were then added and the solution was deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL). The organic layer was washed with brine (2×50 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.19 g, 32%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.79-9.77 (m, 1H), 8.40-8.35 (m, 1H), 8.00-7.92 (m, 1H), 7.54-7.48 (m, 1H), 7.29-7.22 (m, 1H), 7.04-6.96 (m, 2H), 6.66-6.63 (m, 1H), 4.79-4.64 (m, 2H), 3.89-3.83 (m, 2H), 3.79 (s, 3H), 3.72-3.67 (m, 2H), 3.11-2.87 (m, 4H), 2.04-1.99 (m, 1H), 1.31-1.29 (m, 6H), 1.00-0.97 (m, 6H).