Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[NH2:14].[P:15]([N:23]=[C:24]=[S:25])(=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(Cl)(Cl)Cl>[CH2:17]([O:16][P:15]([NH:23][C:24]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][C:24]([NH:23][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])=[S:25])=[C:7]([Cl:6])[CH:12]=1)=[S:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: Nc1ccc(N)c(Cl)c1
Reactant: CCOP(=O)(N=C=S)OCC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(NC(=S)Nc1ccc(NC(=S)NP(=O)(OCC)OCC)c(Cl)c1)OCC

Procedure:
Employing the process of Example 1 in every detail except that 2-chloro-p-phenylenediamine sulfate is neutralized and allowed to react with two equivalents of diethyl phosphoroisothiocyanatidate ##STR7## in chloroform instead of methylene chloride to afford the title compound, m.p. 148°-149° C.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1cn(CCCCO)c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCO)c2ccccc12

Procedure:
Beginning with 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide and 1-(4-hydroxybutyl)indole-3-glyoxylic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49]([O:51]C)=O)=[N:29]2)=[C:24]([F:53])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:40][CH2:41]3)[C:30]([C:49](=[O:51])[NH2:11])=[N:29]2)=[C:24]([F:53])[CH:23]=1
Reactant: COC(=O)c1nn(-c2ccc(Br)cc2F)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)cc3F)nc2C(N)=O)CC1
Yield: 100 %

Procedure:
tert-Butyl 4-(1-(4-bromo-2-fluorophenyl)-3-carbamoyl-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 100% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for Methyl 1-(4-bromo-2-fluorophenyl)-4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-oxo-1,6-dihydropyridazine-3-carboxylate (Example 44). MS (ESI) 511 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH3:13].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ccc(N)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O

Procedure:
Using ethyl 4-amino-3-methylbenzoate (1.0 g) and 3-chloropropane-1-sulfonyl chloride (0.9 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (463 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])=[CH2:11])[CH2:3][C:4]([OH:6])=O.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[O:13][C:4](=[O:6])[CH:3]=1
Reactant: C=C(C)CCC(=O)C(C)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)=CCC1OC(=O)C=C1C

Procedure:
The thus-obtained 3,7-dimethyl-4-oxo-7-octenoic acid is then dissolved in a solvent and an equivalent amount or a somewhat excessive amount of acetic anhydride is added thereto and heated under reflux in the presence of an acid catalyst, whereby the acid is cyclized and dehydrated along with isomerization of the terminal double bond to give 3,7-dimethyl-2,6-octadien-4-olide. As the solvent in this process, usable is a hydrocarbon solvent such as pentane, hexane, heptane, benzene, toluene, xylene or the like. Especially preferred is toluene. As the acid catalyst, usable is an organic acid such as acetic acid, para-toluene-sulfonic acid, camphor-sulfonic acid or the like.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][S:21][CH2:22][C:23](O)=[O:24])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>ClCCl.O.CN(C=O)C>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([NH:40][C:23](=[O:24])[CH2:22][S:21][CH2:20][C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:11]=2[C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:4]=2)[CH:42]=1
Reactant: O=C(O)CSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(CSCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1)Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
141 mg (0.358 mmol) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]-pyridin-2-yl)methylthio)acetic acid were dissolved in 5 ml of dichloromethane followed by the addition of 0.094 ml (1.073 mmol) of oxalyl chloride and a drop of DMF. The solvent was stirred at r.t. for 2 h and then the solvent was evaporated in vacuo. The obtained residue was taken up in 5 ml of tetrahydrofurane, 99 mg (0.715 mmol) of sodium carbonate were added followed by the addition of 40.4 mg (0.429 mmol) of 3-aminopyridine. The solution was stirred at r.t. for 16 h. The mixture was then poured onto 15 ml of water, extracted 3 times with 15 ml of ethyl acetate, the combined organic phases were washed with 20 ml of brine and then were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol gradient, 100% to 90% of dichloromethane, v/v). 89 mg of N-(pyridin-3-yl)-2-((3-((3-(trifluoromethyl)-phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio) acetamide were obtained as a pale yellow solid. LC-MS: m/z=467 (MH+) UV purity at 254 nm=95%. 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 8.76 (dd, J=16.4, 4.5 Hz, 2H), 8.24 (dd, J=4.7, 1.5 Hz, 1H), 8.07 (ddd, J=8.3, 2.5, 1.5 Hz, 1H), 7.79-7.60 (m, 3H), 7.60-7.35 (m, 3H), 7.30 (dd, J=8.3, 4.7 Hz, 1H), 7.16 (td, J=6.8, 1.1 Hz, 1H), 4.90 (s, 2H), 4.26 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]1N1CCOCC1.Cl>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CC1c2cc(O)ccc2OC1N1CCOCC1
Agent: Cl
Product: Cc1coc2ccc(O)cc12
Temperature: 56 °C
Yield: 74.1 %

Procedure:
3-Methyl-2-morpholin-4-yl-2,3-dihydro-benzofuran-5-ol (prepared as above in EXAMPLE II) (628 g, 2.7 mol) was added to hydrochloric acid (HCl) (20%, 2 L) at room temperature with stirring. The reaction mixture was heated to 56° C. for 3 hours and then cooled down. The crude was extracted with toluene (500 mL) for three times. The organic phases were obtained, combined and evaporated to provide a crude product, which was further recrystallization to afford 3-methyl-benzofuran-5-ol (290 g, 2 mol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 34 was prepared from bis(4-methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.29 (d, 2H, J=6.1 Hz), 7.13 (m, 8H), 6.93 (d, 1H, J=7.5 Hz), 6.83–6.78 (m, 1H), 7.27–7.21 (m, 1H), 4.81 (s, 1H), 3.40–3.34 (m, 2H), 2.91 (d, 2H, J=11.6 Hz), 2.53–2.41 (m, 2H), 2.36 (t, 2H, J=6.6 Hz), 2.29 (s, 6H), 1.99–1.88 (m, 2H), 1.78 (d, 3H, J=12.9 Hz), 1.67 (t, 2H, J=6.6 Hz), 1.62–1.56 (m, 1H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 526.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[NH2:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(OCC)C>CS(C)=O>[NH2:13][C:14]1[CH:19]=[C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(O)ccc1N
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc(Oc2ccnc(N)c2)ccc1N
Temperature: 25 °C
Yield: 31.5 %

Procedure:
4-Amino-3-methoxyphenol (5.88 g) was dissolved in dimethyl sulfoxide (80 ml) while stirring, and then 60% sodium hydride (1.6 g) was added thereto gradually under a nitrogen stream, followed by stirring for 20 min. 2-amino-4-chloropyridine (2.75 g) was then added thereto, followed by stirring at 160° C. for 8 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether was then added to precipitate crystals. The crystals were filtered and dried under aeration to provide the titled compound (1.56 g, 34%) as pale brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Br:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2n1
Reaction time: 6 h

Procedure:
A solution is prepared from 1.15 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) in 50 ml of chloroform and 5.3 ml of pyridine and combined dropwise with 1 g (0.33 ml) of bromine in 10 ml of chloroform at room temperature. After 6 hours of agitation, the mixture is concentrated, taken up in 30 ml of water, made alkaline with ammonia, layered over with ethyl acetate, and then shaken and suctioned off. The thus-obtained residue is 0.86 g of 8-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 286°-290° C. (under decomposition).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[C:12]([O:16][C:17](=[O:21])[CH2:18][Zn]Cl)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[CH:3][C:4]=2[CH2:8][O:7]1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)C[Zn]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2c(c1)COC2=O
Temperature: 105 °C

Procedure:
To a 20 mL microwave tube charged with 5-bromo-2-benzofuran-1(3H)-one (500 mg, 2.35 mmol) and palladium tetrakis triphenylphosphine (136 mg, 0.117 mmol) in THF (5 mL) was added (2-tert-butoxy-2-oxoethyl) (chloro) zinc (6.57 mL, 0.5 M, 3.29 mmol). The mixture was purged with nitrogen 3 times, and heated to 105° C. for 30 minutes in a microwave reactor. The reaction mixture was poured into water and filtered then extracted with ethyl acetate twice. The organic layer was ashed with brine, dried, and evaporated to dryness. The residue was purified by MPLC on a 40 g ISCO Redi-Sep column to yield tert-butyl (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (500 MHz, CDCl3) δ ppm 7.89 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 5.33 (s, 2H), 3.69 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [I-].[CH:2]([O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[O:22][CH3:23])=[C:10]([C:24]2[O:25]CC(C)(C)[N+]=2C)[CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[OH-:32].[Na+]>CO>[CH:2]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:24]([OH:25])=[O:32])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:14][C:13]=1[O:22][CH3:23])([CH3:4])[CH3:3]
Reactant: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C1=[N+](C)C(C)(C)CO1
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C(=O)O
Yield: 84 %

Procedure:
Prepare a solution of 2-(6,4'-diisopropyloxy-2 '-methoxy-biphenyl-2-yl)-3,4,4-trimethyl-oxazolinium iodide (13.20 g, 0.0245 mole) in 20% NaOH (140 mL) and methanol (140 mL) and stir at reflux overnight. Concentrate the resulting colorless solution on the rotovap until precipitation begins. Dilute the resulting suspension to 300 mL with water and acidify with concentrated HCl to pH=1. Extract the precipitate into CH2Cl2 (400 mL), wash with brine, separate and dry over MgSO4. Filter, concentrate and recrystallize from cyclohexane (~175 mL) to obtain the title compound (7.10 g, 84%). m.p. 117-119° C.
Reaction SMILES: Cl[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])[O-].[K+].[K+].[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:4])[CH3:3])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(Cl)c1ccccc1
Reactant: c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
541 g of 2-chloro-2-phenylpropane (3.5 mol) were added dropwise at 5° C. with stirring to a suspension of 35 g of clean pulverised aluminium chloride in 3.5 1 of dry benzene in the course of 5 h, and the mixture was kept at 5° C. for a further 15 min. and then poured onto ice. The benzene phase was neutralised with potassium carbonate after separating off the aqueous phase, dried and freed from excess benzene. 650 g of crude product were obtained, which was fractionally distilled through a column about 100 cm long. 527 g (78% of the theoretical yield) of 2,2-diphenylpropane passed over at 152°-160° C. and 20 mbar.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][O:23][C:22]2[CH:36]=[CH:37][CH:38]=[CH:39][C:21]1=2>>[NH2:28][C@H:25]1[CH2:24][O:23][C:22]2[CH:36]=[CH:37][CH:38]=[CH:39][C:21]=2[N:20]([CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[CH3:8])[C:26]1=[O:27]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Reaction time: 2 h
Yield: 77.9 %

Procedure:
TFA (7.68 g, 67.3 mmol, Eq: 28.8) was added to a solution of (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.01 g, 2.34 mmol, Eq: 1.00) and the mixture was stirred 2 h and the solvent removed. The residue was treated with sat. NaHCO3 and the aqueous mixture extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford (S)-3-amino-5-((2-methylnaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (606 mg, 76%) as a white foam.
Reaction SMILES: N1(CCOC2C=CC(NC3SC(C4C=CC(O)=CC=4)=CN=3)=CC=2)CCCC1.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[S:38][C:39]([C:42]3[CH:46]=[CH:45][S:44][CH:43]=3)=[CH:40][N:41]=2)=[C:32]([C:47]([F:50])([F:49])[F:48])[CH:31]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[S:44]1[CH:45]=[CH:46][C:42]([C:39]2[S:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][C:32]=3[C:47]([F:50])([F:49])[F:48])=[N:41][CH:40]=2)=[CH:43]1
Reactant: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 for 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-thiazol-5-yl}-phenol but starting from (4-methoxy-2-trifluoromethyl-phenyl)-(5-thiophen-3-yl-thiazol-2-yl)-amine and using 4 equivalents of BBr3. Title compound: ES-MS: 342.9 [M+H]+; single peak at tR=3.71 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][PH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 75 °C
Yield: 44.9 %

Procedure:
In an embodiment of the invention, a method for preparing the aforesaid alignment film in a laboratory level is illustrated as an example. 10 g of 4-nitrobenzyl bromide is mixed with 12 g of triphenylphosphine and dissolved in 150 ml of a dry tetrahydrofuran solution, heated to 75° C. and agitated under reflux for 48 hours, to obtain 8.2 g of a dry white p-nitrobenzyl triphenylphosphine. The p-nitrobenzyl triphenylphosphine is mixed with 2.6 g of p-nitrobenzaldehyde in a 150 ml tetrahydrofuran solution, and agitated under room temperature for about 24 hours to obtain 4.2 g of p-nitrostilbene. The resultant p-nitrostilbene is mixed with 14.7 g of tin dichloride, dissolved in a mixed solution of 30 ml/40% hydrochloride acid and 100 ml acetone, agitated under the room temperature for about 2 hours and refluxed for 8 hours to obtain p-aminostilbene. The p-aminostilbene is mixed with 9,9′-bianthracyl tetracarboxylic dianhydride in a dry NMP (N-methyl-pyrrolidone) solution under agitation for 24 hours, under protection of nitrogen gas, to obtain the precursor of the polyimide alignment film involved in the embodiment. The precursor is heated to 230° C. to obtain the final alignment film, which is a light sensitive alignment film.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]3([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][O:21][CH2:20]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.ClCCl.C(=O)(O)[O-].[Na+]>[C:26]([SiH2:25][O:24][C:23]([CH3:31])([CH3:30])[C:19]1([N:12]2[C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]4[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11]2)[CH2:20][O:21][CH2:22]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(n2cc(C(=O)c3cncc(N)c3)c3cncnc32)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[SiH2]OC(C)(C)C1(n2cc(C(=O)c3cncc(NC(=O)Cc4ccc(Cl)cc4)c3)c3cncnc32)COC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
(5-Amino-pyridin-3-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (Preparation 216, 30 mg, 0.068 mmol) was dissolved in dry pyridine (2 mL) under nitrogen and to this was added (4-chloro-phenyl)-acetic acid (17 mg, 0.102 mmol), followed by HATU (39 mg, 0.102 mmol). The reaction was heated to 50° C. and stirred overnight. The reaction was cooled to room temperature, diluted with dichloromethane and saturated aqueous sodium bicarbonate was added. The phases were separated and the aqueous layer was extracted with dichloromethane (3×5 mL). The combined organics were concentrated to dryness to afford N-(5-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-chloro-phenyl)-acetamide as a pale yellow solid 35 mg, 87% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:16])([C:13]([OH:15])=O)[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:24][C:13]([C:11]2([CH3:16])[CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:17])[NH:10]2)=[O:15])=[CH:26][C:27]=1[C:33]([F:34])([F:35])[F:36])#[N:30]
Reactant: CC1(C(=O)O)CN(c2ccc(F)cc2)C(=O)N1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CN(c2ccc(F)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 1-(4-fluoro-phenyl)-4-methyl-2-oxo-imidazolidine-4-carboxylic acid (120 mg, 0.50 mmol) in DCM (15 mL) was treated oxalyl chloride (0.09 mL, 1.03 mmol) and one drop of dry DMF. After stirring 1 hour at room temperature, the solvent was removed in vacuo. To this residue, a solution of 4-amino-2-(trifluoromethyl)benzonitrile (277 mg, 1.49 mmol) and triethylamine (0.28 mL, 2.01 mmol) in dry DCM (10 mL) was added. After stirring overnight at room temperature, the mixture was concentrated in vacuo and the residue purified by flash chromatography to afford the title compound as a tan solid (110 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:23]1([C:29]#[C:30][C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Nc1ccc(S(=O)(=O)c2cc(C#Cc3ccccc3)nc(N3CCCC3)c2)cc1
Yield: 64.4 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 112 mg (1.1 mmole) phenylacetylene, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride in 5 ml dimethylformamide and 5 ml diethylamine is refluxed for 2 hours. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from chloroform/ethanol yields 260 mg (64%) pure 4-(2-phenylethynyl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine als a pale yellow solid mp.: 202-204° C.