Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]([CH3:19])[C@@H:15]([CH3:18])[CH2:16]O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[ClH:22].[Cl:1][CH2:16][C@@H:15]([N:14]([CH3:19])[CH2:13][CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1)[CH3:18]
Reactant: COc1ccc(CCN(C)[C@@H](C)CO)cc1OC
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCN(C)[C@@H](C)CCl)cc1OC
Yield: 35.8 %

Procedure:
To a solution of 7.06 g (0.028 mole) of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanol hydrochloride in 100 ml of chloroform was added 4.8 ml (0.067 mole) of thionyl chloride and the reaction was heated to reflux for 3 hr. The reaction was cooled and the solvent was evaporated in vacuo to give 3.09 g of (S)-N-(2-chloro-1-methylethyl)-3,4-dimethoxy-N-methylbenzeneethaneamine hydrochloride as a brown glass (43%).
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].O1CCCC1.[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40]/[CH:41]=[CH:42]/[CH:43]([CH3:47])[CH2:44][CH:45]=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CCCCCC>[CH3:48][CH:39]([CH2:40][CH:41]=[CH:42][CH:43]([CH3:47])[CH2:44][CH:45]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:38][O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(/C=C/CC(C)COCc1ccccc1)CC=O
Agent: [I-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1.52 g. (3.42 mmoles) of isobutyltriphenylphosphonium iodide in 30 ml. of anhydrous tetrahydrofuran was stirred and cooled to 0° C. while 1.55 ml. (3.42 mmoles) of n-butylithium solution in hexane was added. The resulting red solution was stirred for 10 minutes at room temperature then treated with a solution of rac. E-8-benzyloxy-3,7-dimethyl-4-octenal (0.594 g.; 2.28 mmoles) in 10 ml. of anydrous tetrahydrofuran. After stirring at room temperature for 30 minutes, the reaction mixture was treated with water and worked up by extraction with hexane as in Example 1. The semi-solid residue was treated with hexane and filtered to remove insoluble material. The filtrate was concentrated in vacuo to give 0.72 g. of yellow oil. This material was chromatographed on 30 g. of silica gel. Elution with 9:1 parts by volume hexane-ether afforded 0.427 g. (62.5%) of an oil. Evaporative distillation yielded rac. benzyl 2,6,10-trimethyl-undeca-4,8-dien-1-yl ether as a colorless liquid, b.p. 110°-115° C. (bath temperature) (0.03 mm Hg.).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>C(Cl)Cl>[C:7]([C:6]1[C:2]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=2[O:28][CH3:27])=[N:3][S:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[F:26])=[O:17])=[CH:11][CH:10]=1)#[N:8]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Solvent: ClCCl
Product: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C#N)c(OC)c1
Temperature: 73 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
A suspension of 1-[4-(3-chloro-4-cyanoisothiazol-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea (4.3 g, 11.1 mmol) in 15 mL of 2,4-dimethoxybenzylamine was heated to 73° C. for 24 h. The reaction became clear after ˜3 h. The reaction was cooled to RT. The residue was diluted with 300 mL of DCM and was washed with 10% HCl solution two times, saturated Na2S2O5 two times followed by brine. The organic solution was dried with MgSO4, filtered, and concentrated. The crude product was purified by flash silica gel column eluted with 2-5% MTBE in DCM/hexanes (2:1) to obtain the title compound as a light yellow solid (1.19 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3cccc(OC)c3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
The ester from Step 1 (0.300 g, 0.727 mmol) was dissolved in THF-ethanol-water (7:2:1, 10 mL). It was treated with sodium hydroxide (0.29 mL of a 2.5 N solution, 0.727 mmol), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 mL). Ether (10 mL) was added, followed by a few drops of concentrated HCl. The ether layer was separated, and the aqueous phase was extracted with ether (2×10 mL). The ether extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to yield a-white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.23 g, 81%): mp 173.1–177.4° C. 1H NMR (CDCl3/300 MHz) 7.81 (s, 1H), 7.39–7.37 (m, 2H), 7.05–7.04 (m, 2H), 6.97–6.94 (m, 1H), 5.71 (q, 1H, J=6.7 Hz), 3.85 (s, 3H). ESHRMS m/z 383.0278 (M−H, Calc'd. 383.029796). Anal. Calc'd. for C18H12ClF3O4: C, 56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl, 9.48.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.[Br:13][CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20]Br.[I-].[Na+]>CCCCCC.CS(C)=O.CC(C)=O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][N:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[CH3:3]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: BrCCCSCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nc2ccccc2n1CCCSCCCBr
Temperature: 0 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
Part A. Sodium hydride (0.11 g of 50% mineral oil suspension, 4.64 mmol) was washed with hexane, and dried under vacuum, then suspended in dimethylsulfoxide and cooled to 0° C. A solution of 2-methyl-1H-benzimidazole (0.61 g, 4.64 mmol) in dimethylsulfoxide (5 mL) was added dropwise. The ice bath was removed, and the mixture was allowed to stir for 5 hours. A solution of bis(3-bromopropyl)sulfide (Example 366, Part A; 2.56 g, 9.27 mmol) in dimethylsulfoxide (5 mL), along with sodium iodide (0.35 g, 2.32 mmol), were added, and the resulting mixture was heated to 80° C. for 20 hours. It was then cooled to ambient temperature, and poured into 100 mL ethyl acetate. This was washed with water (4×100 mL), and the aqueous phases were back-extracted in sequence with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was separated by flash chromatography (1:1 ethyl acetatehexane, then ethyl acetate, then acetone) to afford 1-[3-(3-bromopropyl)thiopropyl]-2-methyl-1H-benzimidazole as an oil (0.21 g, 0.64 mmol). 1NMR (CDCl3): 7.74-7.23 (4H, m); 4.28 (2H, t, J=6 Hz); 3.52 (2H, t, J=6 Hz); 2.70 (2H, t, J=7 Hz); 2.66 (3H, s); 2.55 (2H, t, J=7 Hz); 2.19-2.02 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a solution of 4-fluoro-2-methylbenzoic acid (4.0 g, 26.0 mmol) in THF (30 mL) in a pressure vessel was added cesium carbonate (8.45 mg, 26.0 mmol) and iodomethane (2.0 M in tert-butyl methyl ether, 13.0 mL, 26.0 mmol). The vessel was sealed and the reaction was stirred at 70° C. for 16 h. After cooling to rt, the reaction was quenched with saturated sodium bicarbonate (10 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), and then the organic phase was dried (Na2SO4) and concentrated under reduced pressure to give the crude product. This material was triturated with acetone and hexanes to afford pure product (3.8 g, 87%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 2.60 (s, 3H), 3.86 (s, 3H), 7.05-7.12 (m, 2H), 7.96 (s, 1H); ES-MS m/z 168.2 (MH+); HPLC RT (min) 3.20.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
Pigmentary quinacridone was prepared exactly as described in comparison Example 2 except that 10% by weight, relative to the 2,5-dianilinoterephthalic acid, of 2,5-di(sulfamoylanilino)terephthalic acid (6 g) was included in the ring-closure reaction. Quinacridone (50.2 g) was obtained as a violet pigment.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=1
Reactant: BrBr
Reactant: Oc1ccccc1OC(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.55 mL (30.3 mmol) bromine in 50 mL DCM is added dropwise to a solution of 5.0 g (28.1 mmol) 2-trifluoromethoxy-phenol in 70 mL DCM at −78° C. The reaction solution is heated to RT and stirred for a further 48 h. Then 70 mL Na2SO3 solution are added and the mixture is stirred until the orange colour has disappeared. The solution is diluted with DCM, the organic phase is washed with NaCl solution, dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: PE to PE:EtOAc 4:1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A suspension of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (3.1 g, 16.73 mmol) and manganese dioxide (7.27 g, 83.67 mmol) in DCM (40 mL) was stirred at room temperature for 12 hours. The resulting precipitate was filtered off, and the filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.8 g, 91%) as a yellowish solid. MS (ES+) C7H9N3OS requires: 183. Found: 184 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[N:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:24])(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cn2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cc3)cn2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]ethylcarbamate (step 5) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.20 (1H, br.s), 7.83-7.77 (22H, m), 7.63-7.26 (9H, m), 6.68 (1H, br.s), 3.52-3.45 (2H, m), 2.84-2.79 (2H, m), 2.48 (3H, s), 2.67 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:28])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH2:29]([N:31]([CH2:40][CH3:41])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:30].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(=O)(O)[O-].[Na+]>C(#N)C.CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:28])=[C:4]([C:5]([N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][N:31]([CH2:40][CH3:41])[CH2:29][CH3:30])[CH2:35][CH2:36]2)=[O:7])[CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Reactant: CCN(CC)CCN1CCNCC1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4[nH]nc(-c5ccccc5OC)c4c3)cc(Cl)c2O)CC1
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 4.7 %

Procedure:
14 mg (35 mol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 22 μL (approx. 120 μmol; density unknown) of 1-(2-diethylaminoethyl)-piperazine were dissolved in a mixture of 1 mL of acetonitrile and 100 μL of DMF. 14 mg (55 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the mixture heated gently until all materials were dissolved. The resulting solution was left at ambient temperature for 4.5 h. 28 mg (110 μmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride was added and the resulting mixture left at ambient temperature for 3.5 h, then heated to 75° C. for 3.5 h. The resulting mixture was distributed between 1 mL of a saturated aqueous solution of sodium bicarbonate in water and 2 mL of ethyl acetate. The organic phase was evaporated and the residue directly purified by mass-triggered reverse-phase HPLC to afford 3.2 mg (5.7 μmol, 17%) of {3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.80 (s, br. 1H), 8.81 (d, 1H), 8.29 (d, 1H), 7.82 (d, 1H), 7.64 (dd, 1H), 7.49-7.44 (m, 2H), 7.21 (d, 1H), 7.10 (ddd, 1H), 3.83 (s, 3H), 3.40-3.30 (m, 4H), 2.49-2.35 (m, 8H), 0.94 (t, 6H), MS: m/z 563.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(O)(=O)C.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>O>[CH2:1]([O:3][C:4]([NH:6]/[N:7]=[C:15](/[CH3:17])\[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)N/N=C(/C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazinecarboxylic acid ethyl ester (4.40 g, 42.2 mmol) and acetic acid 60 um, 1.0 mmol) were added to 20 mL (excess) of methyl isopropyl ketone, and the mixture was stirred at room temperature for 18 hours. Water (40 mL) was added, and the mixture was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.25 g of crude N′-[1,2-dimethyl-prop-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester as an oil, which was used directly in the next step.
Reaction SMILES: C1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=CC=CC=3)[C:6](=O)[C:5]=2C=CC=1.[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[C:25]([NH2:35])[C:26]([Br:34])=[CH:27][C:28]=3[OH:33])[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[CH:20][C:19]=1Br>>[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[C:25]([NH2:35])[C:26]([Br:34])=[CH:27][C:28]=3[OH:33])[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[CH:20][C:19]=1[O:15][C:13]1[CH:14]=[CH:5][CH:6]=[CH:7][CH:12]=1
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1c(O)cc(Br)c(N)c1C2=O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: Nc1c(Br)cc(O)c2c1C(=O)c1c(O)cc(Oc3ccccc3)c(N)c1C2=O

Procedure:
When the process according to Example 190a is carried out and, instead of the anthraquinone component mentioned there, 11.7 g of 1,5-diamino-4,8-dihydroxy-2,6-dibromoanthraquinone, compare Example 348a, are used, then 3.8 g, corresponding to 31% of theory, of 1,5-diamino-4,8-dihydroxy-2-phenoxy-6-bromoanthraquinone are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])=[N:34][CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:32]4[O:36][C:35]([Si:37]([CH:41]([CH3:43])[CH3:42])([CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:39])[CH3:40])=[N:34][CH:33]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Product: CC(C)[Si](c1ncc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)(C)C)CC2)O3)o1)(C(C)C)C(C)C

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.62 min; Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:28])([F:27])[CH:24](O)O.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:22][C:23]([F:28])([F:27])[CH2:24][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NCC(F)(F)F)c3)c12
Reaction time: 16 h

Procedure:
To a mixture of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate and 2,2,2-trifluoroethane-1,1-diol in CH2Cl2 (242 μL) at 0° C. was added sodium cyanoborohydride (32.0 mg, 0.509 mmol). The reaction mixture was allowed to stir for 16 hours and then neutralized with 2M aqueous sodium carbonate and extracted with ethyl acetate (×3). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions containing the desired product were concentrated until only the water layer remained. The water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2,2,2-trifluoroethyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C17H16F3N4O2 [M+H]+: 365, found 365. 1H NMR (600 MHz, DMSO-D6) δ 12.92 (s, 1H), 8.87 (s, 1H), 8.25 (s, 1H), 7.21 (t, 1H, J=7.63 Hz), 7.00 (s, 1H), 6.86 (m, 2H), 6.37 (m, 1H), 3.94 (m, 2H), 3.83 (q, 2H, J=7.04 Hz), 0.81 (t, 3H, J=7.04 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10](Cl)=[N:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].[SH2:14].[K].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10](=[S:14])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2sc(Cl)nc2c1
Reactant: S
Agent: Cl
Agent: [K]
Solvent: CCO
Product: CC(=O)c1ccc2sc(=S)[nH]c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A mixture of 5-acetyl-2-chlorobenzothiazole (137 mg, 0.65 mmol), potassium hydrogen sulfide (94 mg, 1.30 mmol) and ethanol (3.3 mL) in a capped flask was stirred in an oil bath at 80° C. for two hours. The mixture was cooled in ice, acidified with 1N hydrochloric acid (1.35 mL) and evaporated in vacuo. The residue was partitioned between water (25 mL) and ethyl acetate (50, 25 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to a solid (133 mg). This material was triturated with ether and dried to provide 5-acetyl-2-thioxo-2,3-dihydrobenzothiazole (110 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH2:30][CH2:31][CH3:32])[CH:35]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCOc1cccc(C=O)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 99.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-propoxybenzaldehyde (623 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (804 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (412 mg) as yellow oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH:16][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Clc1ncccn1
Reactant: Nc1cccc(-c2cnc3ccccn23)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cnc(Nc2cccc(-c3cnc4ccccn34)c2)nc1
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture 3-imidazo[1,2-a]pyridin-3-yl-phenylamine (210 mg, 1.0 mmol), 2-chloropyrimidine (115 mg, 1 mmol) and NaOtBu (100 mg, 1.0 mmol) in dry dioxane (2 ml) was stirred and heated at 100° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The layers were separated and the aqueous layer was extracted with EtOAc (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (20 mg, solid). MS: [M+H]+ 288