Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COB([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)O.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-].[K+].[K+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][O:13][C:11](=[O:12])[C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccncc1
Reactant: COB(O)c1ccc(C(=O)O)cc1
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccncc2)cc1

Procedure:
4-Carboxybenzeneboronic acid methyl ester (248 mmol) from A, 4-bromopyridine (248 mmol), tetrakis-(triphenylphosphin)-palladium (2.5 mmol) and potassium carbonate (744 mmol) are suspended in 1,2-dimethoxyethane (1100 ml). The stirred mixture is heated under reflux for 8 hours. After cooling the solvent is evaporated and water is added to the residue which is then extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale-brown powder with mp. 99-101° C., Rf=0.39 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>C1C=CC=CC=1.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25]
Reactant: CCCCCCC(=N)N
Reactant: S=C=Nc1ccccc1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccccc1Cl

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 300 ml. acetone, 24.7 g. heptanamidine hydrochloride, and 25.9 g. 2-chlorophenyl isothiocyanate (b.p. 70°-74°C./0.5-1.0 mm.; prepared from 2-chloroaniline) in 125 ml. dry acetone there was obtained 1-(2-chlorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 75°-77°C. (from benzene-n-hexane); hydrochloride (33.5 g.), m.p. 158°-160°C. (from acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[P:18]([OH:21])([OH:20])[OH:19].Cl>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:10]([NH:17][CH:6]([P:18](=[O:19])([OH:21])[OH:20])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OP(O)O
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=P(O)(O)C(NCc1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of the imine of ρ-chlorobenzaldehyde and benzylamine (44 g) and phosphorous acid (15.7 g) was heated with stirring. The mixture became liquid and homogeneous at 75°-80° and at 100°-115° reaction commenced raising the temperature to 140°-150°. Upon cooling the reaction mass set to a glass which was dissolved in aqueous sodium carbonate solution. Addition of hydrochloric acid precipitated a white solid which upon drying yielded N-benzyl α-amino ρ-chlorobenzylphosphonic acid, mp 226°-30°, 52 g. ##STR30##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added pyridine-3-sulfonyl chloride (385 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 419.3.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]2[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][CH2:27]Cl>C1COCC1>[C:13]1([C:19]2([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OCCC1c1ccccc1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCC1(c2ccccc2)CCOC1=O
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Butyl lithium (62.5 mL of 1.6M solution in hexanes) was treated dropwise with a solution of diisopropylamine (14.0 mL) in THF (200 mL) at −20° C. and the resulted mixture was stirred for additional 30 min at the same temperature. After that the mixture was cooled to −90° C., treated dropwise with a solution of 2-phenyl-γ-butyrolactone (11.0 g) in THF (50 mL) and then stirred for 45 min at the same temperature. Next the reaction mixture was treated dropwise with a solution of chloromethyl methyl ether (8.05 g) in THF (50 mL), stirred for additional 10 min, then allowed to slowly warm-up to room temperature and stirred at this temperature for 16 h. Subsequently the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated aqueous solution of potassium bicarbonate, then water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.5 g (82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]/[C:10](=[N:13]/[H])/[NH:11][OH:12])=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:13]=[C:35]([CH2:34][N:17]3[CH2:18][CH2:19][CH2:20][C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]3=[O:15])[O:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: [H]/N=C(/CCc1ccc(Cl)cc1)NO
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1N(Cc2nc(CCc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
(Z)-3-(4-Chlorophenyl)-N-hydroxypropanimidamide (0.070 g, 0.352 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.109 g, 0.352 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.135 g, 0.705 mmol) were stirred together in dichloromethane (0.5 mL) at room temperature for 2 hours, then heated to 85° C. overnight. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.39-7.04 (m, 14H), 4.83 (s, 2H), 3.54 (t, J=6.5, 2H), 3.11-2.99 (m, 4H), 2.74-2.61 (m, 2H), 1.99-1.76 (m, 2H); MS (ESI+) m/z 472.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32]([N:39]1[CH:43]=[CH:42]N=[CH:40]1)(N1C=CN=C1)=[O:33].N1CC[CH:47]([C:50]2[C:51](=[O:60])[NH:52][C:53]3[C:58]([CH:59]=2)=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:46]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:39]2[CH2:40][CH2:46][CH:47]([C:50]3[C:51](=[O:60])[NH:52][C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:42][CH2:43]2)=[O:33])[CH2:18][CH2:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 67 %

Procedure:
Triethylamine (50 μL, 0.358 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (60 mg, 0.143 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in tetrahydrofuran (3 mL) at 0° C. After 25 min, 3-piperidin-4-ylquinolin-2(1H)-one (33 mg, 0.143 mmol) and dichloromethane (3 mL) were added and the mixture heated to 60° C. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)]. Repurification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (57.5 mg). MS 601.2312 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:3]=[N:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1
Product: Nc1ccc(-c2cnn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-pyrazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.11) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.027 g, 0.6%). MS (ISP) 451.1 [(M+H)+]; mp 206° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.C([O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39])(C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][CH2:37][C:36]([OH:35])=[O:40])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:13][CH2:12]1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)CCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NCCC(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 1 Step D (0.1 mmol, 41 mg), the hydrochloride salt of β-alanine tert-butyl ester (0.15 mmol, 27 mg), HOBt (0.25 mmol, 38 mg) and EDC (0.4 mmol, 77 mg) in 1 mL of DMF was added DIEA (0.5 mmol, 90 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then partitioned into EtOAc/H2O. The aqueous phase was washed with EtOAc, and the combined organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was treated with 3 mL of 2:30:68H2O/TFA/DCM for 1 hr and the solution was concentrated under reduced pressure. Purification by reverse-phase chromatography (Condition A), followed by lyophilization, afforded the product as a white solid. MS (ESI): m/z 477 (M+H). HPLC A: 1.70 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[C:9](=[O:12])[O:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc(C(F)(F)F)cc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(C(F)(F)F)cc21
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 6-(trifluoromethyl)isobenzofuran-1(3H)-one (prepared as described in the previous step, 5.5 g, 27.23 mmol, 1.00 equiv) in CCl4 (10 mL), NBS (5.8 g, 32.58 mmol, 1.20 equiv) and AIBN (0.45 g, 0.10 equiv). The reaction mixture was stirred for 3 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate, washed with 60 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:16])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:17]I>C(Cl)(Cl)Cl>[I-:17].[CH3:16][C:12]1[C:13]2[C:8](=[S+:7][C:6]3[C:15]([N:14]=2)=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=3)[CH:9]=[CH:10][CH:11]=1
Reactant: II
Reactant: Cc1cccc2c1Nc1c(C)cccc1S2
Solvent: ClC(Cl)Cl
Product: Cc1cccc2[s+]c3cccc(C)c3nc12
Product: [I-]
Reaction time: 8 h

Procedure:
1,9-Dimethylphenothiazine (4.2026 g, 18.49 mmol) was dissolved in 130 mL of chloroform and crushed iodine (14.1 g, 55.55 mmol, 3 eq.) dissolved in 520 mL of chloroform was added over 2 hurs. Once newly formed precipitate was filtered off or the solvent removed under vacuum, the resulting iodide salt was stirred with ether or hexane (sometimes overnight) to remove excess iodine then refiltered. After pumping down under vacuum, a brown precipitate was obtained as product (12.6 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>C(#N)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: COc1cccc(CN)c1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-methoxybenzylamine and acetonitrile essentially as described above in example 35, except that the column is eluted with a graded solvent mixture of 50% ethyl acetate in heptane to 100% ethyl acetate. Purity by LC/MS (APCI)=99%, [M+H]+=381.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[CH:12]([NH:15][S:16]([Cl:19])(=[O:18])=[O:17])([CH3:14])[CH3:13].C(Cl)Cl>O>[CH3:11][O:10][C:8]([N:15]([CH:12]([CH3:14])[CH3:13])[S:16]([Cl:19])(=[O:18])=[O:17])=[O:9]
Reactant: COC(=O)Cl
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N(C(C)C)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
39.6 parts of pyridine are added in the course of 15 minutes at 10° C., whilst stirring, to a mixture of 47.2 parts of methyl chloroformate and 78.8 parts of isopropylsulfamic acid chloride in 330 parts of methylene chloride. The reaction mixture is then stirred for 10 minutes at 22° C. Thereafter, the mixture is stirred for 8 minutes with 350 parts of water at 6° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 72.1 parts (67% of theory) of N-methoxycarbonyl-N-isopropylsulfamic acid chloride, of boiling point 60°-64° C./0.13 mbar and nD25 =1.4540, are obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[C:43]([Zn])#[N:44]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:43]([C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1)#[N:44]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: N#C[Zn]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C#N)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 120 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0. 113 mmol), tetrakis(triphenylphosphine) palladium(0) (13.1 mg, 0.011 mmol) and cyanozinc (20.7 mg, 0.226 mmol) were combined in dry N,N-dimethylformamide (2 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 21 mg (30.5%) as an oil. LC/MS (HPLC method 2): tR=3.265 min, 609.18(MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[O:9].O[C:11]1C=CC(C2C=CC(O)=CC=2)=CC=1>O1CCOCC1>[O:9]1[C:8]2[CH:11]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=[CH:2][NH:1]1
Reactant: Nc1ccccc1
Reactant: C=O
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: C1COCCO1
Product: C1=Cc2ccccc2ON1
Yield: 292.5 %

Procedure:
To a flask of 0.5 L in volume, 71.7 g (0.77 mol) of aniline and 150 mL of dioxane were placed and the mixture was stirred to dissolve. Then, 37.3 g of a formaldehyde solution (a 36 to 38% aqueous solution) was added dropwise to be reacted at room temperature for 2 hours. Thereafter, 71.5 g (0.38 mol) of 4,4′-dihydroxybiphenyl was added to be reacted with stirring at 100 to 110° C. for 6 hours. After completion of the reaction, a precipitate was filtrated and dried in a vacuum drier at 95° C. for 8 hours to obtain 148 g of the compound (E-1) having at least two benzoxazine rings and represented by the formula (15) below.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[NH2:25]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[NH:25][C:4]1[C:3]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[C:22]([Cl:21])[CH:23]=2)=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: N#Cc1ccc(Nc2c(F)c3c(c(F)c2Nc2ccc(C#N)c(Cl)c2)C(=O)c2ccccc2C3=O)cc1Cl
Reaction time: 8 h

Procedure:
1,2,3,4-Tetrafluoroanthraquinone and 25 g of 3-chloro-4-cyanoaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 150° C. for about 8 hours. After completion of reaction, 3-chloro-4-cyanoaniline was distilled out from the reaction solution and a column purification using a column with a silica gel was effected to give rise to 1.14 g of 2,3-bis(3-chloro-4-cyanoanilino)-1,4-difluoroanthraquinone (Dye 22') (yield 29.3 mol %). The physical properties of Dye 22' and analytical values defining the compound are tabulated in Table 23.
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[Cl:10][C:11]1[C:12](O)=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=O.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][NH:25][CH3:26]>O>[Cl:10][C:11]1[C:12]([Cl:8])=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([N:25]([CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[CH3:26])=[O:18]
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: CNCCN(C)C
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
N,N-dimethylformamide (0.05 ml, 0.65 mmol) was added to a thionyl chloride solution (10 ml) of 5-chloro-6-hydroxynicotinic acid (1.0 g, 5.76 mmol), and stirred under a nitrogen atmosphere at 90° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and with cooling with ice, N,N,N′-trimethylethane-1,2-diamine (2.32 ml, 17.3 mmol) was added to an N,N-dimethylformamide solution (10 ml) of the obtained residue, and stirred at room temperature for 3 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 go 1:1) to obtain 5,6-dichloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (1.59 g, yield: 100%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32].CO>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A solution of 200 mg (0.52 mmol) of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl) -4H-1,2,4-triazole (from Step A) in 2 ml of dry DMF was treated with 21 mg (0.52 mmol) of sodium hydride (60% in oil), and the mixture was stirred under N2 at room temperature for a few minutes until H2 evolution had ceased and a clear solution had resulted. To this was added 119 mg (0.52 mmol) of methyl α-bromophenylacetate, and stirring was continued under N2 at room temperature for 10 minutes and then at 65° C. for 6 hours. The cooled mixture was treated with 1 ml of MeOH and then concentrated in vacuo. The residue was partitioned between 25 ml of EtOAC and 30 ml of H2O. The EtOAc phase was washed with 2×25 ml of H2O and then with 25 ml of saturated NaCl. The organic solution was dried over MgSO4, filtered, and concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.75-1.2% MeOH in CH2Cl2) yielded 191 mg (69%) of the title compound as a glass; homogeneous by TLC in 97:3 CH2Cl2 -MeOH.