Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:23]2[C:14](=[CH:15][C:16]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:22]=2)[O:13][CH2:12]1.[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2([C:36]3=[CH:37]C4OCOC=4C=C3OC2)C1=O.Br.BrCC1C=CC=CN=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:27]=[CH:26][CH:36]=[CH:37][N:24]=1)[C:8](=[O:11])[C:7]12[C:23]2=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=[C:14]2[O:13][CH2:12]1
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(Cc2ccccn2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (38%) as a colorless solid: mp 205-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ8.55 (d, J=4.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.23-7.16 (m, 2H), 6.99-6.89 (m, 3H), 6.50 (s, 2H), 5.35 (d, J=16.4 Hz, 1H), 5.17 (d, J=16.4 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.22-4.19 (m, 2H), 4.15-4.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 155.7, 155.1, 149.6, 144.7, 138.4, 136.7, 124.0, 124.0, 122.4, 121.0, 120.7, 119.7, 119.6, 116.7, 116.5, 112.1, 99.3, 80.3, 64.5, 63.9, 58.4, 47.0; MS (ES+) m/z 405.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([OH:17])[CH:3]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>ClC1C=CC=CC=1Cl>[ClH:18].[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)cc1C
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(=O)c3ccccc3)c2cc1OC
Product: Cl
Temperature: 180 °C
Yield: 11.6 %

Procedure:
(4,5-Dimethyl-2-methoxyphenyl)(phenyl)methanone (650 mg) was dissolved in dimethylformamide (10 ml) to prepare a solution. Sodium thiomethoxide (379 mg) was added to the solution, and the mixture was stirred while heating under reflux overnight. The reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate and was concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone. The (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone (40 mg) thus obtained and 4-chloro-6,7-dimethoxyquinoline (150 mg) were added to o-dichlorobenzene (0.2 ml), and the mixture was heated at 180° C. for two days. The reaction solution was concentrated and was subjected to separation and purification by column chromatography on silica gel using hexane-ethyl acetate. Subsequently, a hydrochloric acid-methanol mixed solution was added thereto, the solvent was removed by distillation, and the residue was suspended in ethyl acetate. The solid thus obtained was collected by filtration, was washed with ethyl acetate, and was then dried to give the title compound (9.2 mg, yield 11%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](C(OC)=O)=[CH:2]1.[N:10]1[O:11][N:12]=[C:13]2[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][C:14]=12.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[N:10]1[O:11][N:12]=[C:13]2[C:18]([CH:19]3[C:13]([C:14]#[N:10])=[C:18]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[NH:21][C:22]4=[N:23][NH:24][CH:25]=[C:26]34)=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: O=Cc1cccc2nonc12
Reactant: COC(=O)c1ccoc1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(c2ccco2)Nc2n[nH]cc2C1c1cccc2nonc12

Procedure:
The title compound was prepared from methyl furan-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=2[CH3:15])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[Cu](C#N)[C:17]#[N:18].O.C(OCC)(=O)C>CN(C)C=O>[N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:17]#[N:18])=[CH:10][C:9]=2[CH3:15])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)ccc1C(=O)N1CC=CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1C(=O)N1CC=CC1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
31.6 g (0.11 mol) of 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbromobenzene is dissolved in 125 mL of dimethylformamide and combined with 20.2 g (0.23 mol) of copper cyanide and 3.2 g (2.7 mmol) of tetrakis-triphenylphosphinepalladium(0). The suspension is stirred for 20 hours at 140° C. Then it is cooled to 80° C., combined with 150 mL of water, 150 mL of ethyl acetate, and 25 g of CELITE® filter aid and filtered through CELITE® filter aid. The organic phase is separated off, washed with sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/ethanol (50:1 and 19:1). The corresponding fractions are combined and concentrated by evaporation. Yield: 11.7 g (49% of theory); Rf value: 0.55 (silica gel; ethyl acetate/ethanol=9:1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH2:28](O)[CH3:29].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([O:24][CH2:28][CH3:29])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 86 %

Procedure:
To a mixture of (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.3 g) and ethanol (50 ml) was added conc. sulfuric acid (0.1 ml). The mixture was heated for 8 hours under reflux, then the reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v), ethyl (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvate (1.2 g, 86%) was obtained. Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point: 110-111° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH:33]=O>>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: O=Cc1cc2ccccc2[nH]1
Product: CCCN(CCN1CCN(Cc2cc3ccccc3[nH]2)CC1)C1CCc2ccc(O)cc2C1
Yield: 87.5 %

Procedure:
Compound 40d was prepared according to Procedure A using 39a (100 mg, 0.32 mmol) and 1H-Indole-2-carbaldehyde (100 mg, 0.69 mmol) to give 40d (125 mg, 85%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J=7.2 Hz), 1.39-1.50 (m, 3H), 1.89 (brs, 1H), 2.41-2.73 (m, 18H), 2.82-2.88 (m, 1H), 3.65 (s, 2H), 6.35 (s, 1H), 6.44 (brs, 1H), 6.54-6.57 (m, 1H), 6.87 (d, 1H, J=8.8 Hz), 7.04-7.08 (m, 1H), 7.10-7.16 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 7.54 (d, 1H, J=8.0 Hz), 8.63 (s, 1H). The free base of 40d was converted into oxalate salt. m.p. 135-137° C. Anal. [C28H38N4O.3.0(COOH)2.0.3H2O] C, H, N.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:49]1([C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])=[O:56])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.O>[O:25]=[C:23]([N:52]1[CH2:53][CH2:54][N:49]([C:55](=[O:56])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:64])[F:65])[CH2:50][CH2:51]1)[CH2:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[CH:12]2)=[O:20]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
DIPEA (0.111 mL, 0.64 mmol) was added to a stirred solution of [(1H-Indole-5-carbonyl)-amino]-acetic acid (40 mg, 0.18 mmol) in DMF (1.0 mL). HOBT (29 mg, 0.22 mmol) and EDCI.HCl (42 mg, 0.22 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (59 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered to afford 1H-Indole-5-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 45% yield. LC-MS purity: 91%, 1H NMR (CDCl3): δ 8.48 (s, 1H), 8.18 (s, 1H), 7.78-7.54 (m, 4H), 7.42-7.30 (m, 2H), 7.28 (s, 1H), 6.62 (s, 1H), 4.40-4.20 (m, 2H), 4.18-3.82 (m, 2H), 3.78-3.52 (m, 4H), 3.24 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][NH:8][C@H:7]([C:15]([OH:17])=[O:16])[CH2:6][C:5]2=1.[C:18](=[S:20])=[S:19].[CH3:21]I.Cl>CS(C)=O.O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][N:8]([C:18]([S:20][CH3:21])=[S:19])[C@H:7]([C:15]([OH:17])=[O:16])[CH2:6][C:5]2=1
Reactant: S=C=S
Reactant: CI
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CSC(=S)N1Cc2[nH]c3ccc(F)cc3c2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
65 mg of (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid are dissolved in a mixture of one ml of dimethylsulfoxide and 0.5 ml of water. 0.02 ml of carbon disulfide and 0.093 ml of triethylamine are added to the mixture, and the mixture is stirred at room temperature for 20 minutes. 0.021 ml of methyl iodide is added to the mixture, and the mixture is stirred at room temperature for 16 hours. Water is added to the mixture, and the aqueous solution is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel thin layer chromatography (Solvent; chloroform:methanol:acetic acid=93:6:1). 37 mg of (3S)-6-fluoro-2-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid are obtained as pale yellow powder.
Reaction SMILES: C(O[C:4]([CH2:6][C:7](=O)[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:5])C.Cl.[O:30]([NH2:32])[CH3:31].[C:33](OCC)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH2:33]([O:35][C:6](=[C:4]=[O:5])[C:7](=[N:32][O:30][CH3:31])[CH2:8][O:9][N:10]=[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH3:34]
Reactant: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CON
Reactant: CCOC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=C=O)C(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)=NOC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.85 g of the 4,4'-dimethoxybenzophenone O-(3-ethoxycarbonyl-2-oxopropyl) oxime as obtained in Example 1 was dissolved in 5 ml of pyridine and 1 g of methoxylamine hydrochloride was added thereto. Then the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into ethyl acetate, washed with diluted hydrochloric acid and then with a saturated saline solution and purified by silica gel chromatography. Thus 4 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([CH:14]2C(=O)OC(C)(C)OC2=O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O1CCOCC1>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:13])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)C2C(=O)OC(C)(C)OC2=O)C1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.05 mmol) in a mixture of actic acid (0.5 mL), water 0.25 mL and dioxane (3 mL) was stirred under microwaves at 100° C. for 30 minutes. After concentration to dryness, the residue was coeveoparted with dichloromethane (2×100 mL). The title product was obtained as a colorless gum (600 mg, 100%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)cc2C)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Yield: 99 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (61.5 mg, 0.0983 mmol) prepared in Example 172a, triethylsilane (0.079 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound (42.0 mg, 99%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([CH:40]=2)[NH2:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([NH:39][C:24]([C:16]3[C:17]4[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=4[C:12]4[NH:11][C:10]([NH:9][C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:14][C:13]=4[CH:15]=3)=[O:25])[CH:40]=2)[CH2:33][CH2:32]1
Reactant: Nc1cc(C2CC2)ccc1F
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C4CC4)ccc3F)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 14.9 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.100 g, 0.255 mmol), thionyl chloride (1.0 mL), 5-cyclopropyl-2-fluoro aniline (Intermediate-47, 0.077 g, 0.511 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 1.0-2.0% MeOH:DCM to afford 0.020 g of the desired product 1HNMR (DMSO-d6): δ 0.62 (m 2H), 0.94 (d, J=6.3 Hz, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.11 (s, 2H), 6.80 (m, 1H), 7.17 (m, 2H), 7.54 (m, 3H), 8.22 (s, 1H), 10.04 (s, 1H), 11-11.5 (s, 2H); MS [M]+: 525.15.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1.[Br:19]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][Br:19])[CH:8]=1
Reactant: Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1

Procedure:
A mixture of 22.6 g (0.07 mole) of 2-bromo-5-chloro-3-(3-methylphenyl) benzofuran, 12.5 g (0.07 mole) of N-bromosuccinamide in 500 ml of carbon tetrachloride is irradiated and heated with a sun lamp for about 20 hours. The reaction mixture is filtered hot and the filtrate is allowed to cool. A solid forms which is collected, washed with carbon tetrachloride, and dried, then recrystallized from ethyl acetate to provide white product, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran, which is used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[S:12][C:13]1[C:14]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[C:15]([O:32][CH3:33])[CH:16]=[CH:17][C:18]=1[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[NH:45]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:46]([C:54](O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:60]([O:59][C:57]([NH:45][C@H:46]([C:54]([CH:9]([NH2:8])[C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[S:12][C:13]1[C:14]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])=[C:15]([O:32][CH3:33])[CH:16]=[CH:17][C:18]=1[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:58])([CH3:62])([CH3:63])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCN1c2ccc(OC)c(CN)c2Sc2c1ccc(OC)c2CC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN1c2ccc(OC)c(CC(=O)OCc3ccccc3)c2Sc2c1ccc(OC)c2C(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
72.8 mg of benzyl (6-aminomethyl-3,7-dimethoxy-10-hexylphenothiazin-4-yl)-acetate trifluoroacetate were reacted with 39.7 mg of Boc-Phe-OH analogously to that described in Example 4.7.1. The crystalline benzyl [6-((N-tert.-butoxycarbonyl-L-phenylalanyl)-aminomethyl)-10-hexyl-3,7-dimethoxyphenothiazin-4-yl]-acetate obtained was dissolved in trifluoroacetic acid, whereupon the solution was left to stand at 20° for 10 minutes and concentrated in a vacuum. The residue was dissolved in 3 ml of DMF, whereupon 84.3 mg of Z-Tyr(Bzl)-ONp were added and the pH value was adjusted to 8.5 with DIPEA. After 3 hours the reaction mixture was worked up as described in Example 4.7.1. The crystalline benzyl [6-(((N,O-bis-benzyloxycarbonyl-L-tyrosyl)-L-phenylalanyl)-aminomethyl)-10-hexyl-3,7-dimethoxy-phenothiazin-4-yl]-acetate obtained was further processed analogously to that described in Example 2.2.1., whereby the crude product was crystallized from ethanol. 21.3 mg of 10-hexyl-3,7-dimethoxy-4,6-cyclo-[acetyl-L-tyrosyl-L-phenylalanyl-aminomethyl]phenothiazine were obtained; MS: 723.5 MH+.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH2:17])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16].[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C@H:2]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH:17][C:27]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:34])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a slurry of N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.250 g, 0.70 mmol) and nicotinic acid (0.107 g, 0.87 mmol, 1.3 equiv.) in DMF (10 mL) was added PyBOP (0.452 g, 0.87 mmol, 1.3 equiv.) followed by diisopropylethylamine (0.48 mL, 2.78 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature. After a few hours the mixture turned to a clear solution. The resulting solution was stirred at room temperature for 24 h, then was concentrated under reduced pressure. The residue was separated between water (25 mL) and a 4:1 CH2Cl2/isopropanol solution (50 mL). The resulting organic phase was washed with a saturated sodium bicarbonate solution, dried (anh. sodium sulfate) and concentrated under reduced pressure. The resulting material (0.588 g) purified using MPLC to afford N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.16 g, 50%): HPLC ret. time 1.00 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.83-1.93 (m, 2H), 1.93-2.05 (m, 2H), 3.04-3.15 (m, 2H), 3.29-3.34 (m, 2H), 3.53-3.62 (m, 2H), 4.03 (s, 3H), 4.20-4.32 (m, 5H), 4.53-4.60 (m, 2H), 7.48 (d, J=9.1 Hz), 7.88 (dd, J=5.6, 8.1 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.84, (br d, J=8.1 Hz, 1H), 8.94 (dd, J=1.5, 5.3 Hz, 1H), 9.47 (d, J=1.5 Hz, 1H); mass spectrum m/z 465 ((M+1)+, 17%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[S:3]1(=[O:17])=[O:16].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].Cl>CN(C)C=O>[OH:8][C:6]1[C:5]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[S:3](=[O:17])(=[O:16])[N:2]([CH3:1])[C:7]=1[C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C=Nc1ccccc1
Reactant: CN1CC(=O)c2sc3ccccc3c2S1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Temperature: 27 °C
Reaction time: 2 h

Procedure:
2.67 g. of 3,4-dihydro-2-methyl-4-oxo-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide are dissolved in 40 ml. of absolute dimethylformamide and 1.2 ml. of phenylisocyanate are added. The solution obtained is added dropwise at 4° C. within 30 minutes to a suspension of 600 mg. of a 55% sodium hydride dispersion in paraffin in 10 ml. of dimethylformamide. The mixture is stirred for a further 1 hour at 4° C. and subsequently for 2 hours at 27° C. and then stirred into 400 ml. of ice/water. The solution obtained is acidified with concentrated hydrochloric acid. The precipitate is filtered off under suction, washed with water and dissolved in methylene chloride. The resulting solution is dried over sodium sulfate and evaporated. The residue is stirred with 30 ml. of methanol. The insoluble components are digested with acetonitrile, filtered off under suction and dried for 4 hours at 100° C./11 Torr. The 4-hydroxy-2-methyl-N-phenyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide obtained melts at 261°-263° C.