Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclopropanecarbonyl chloride (20 mg, 192 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (11.8 mg, 38% of theory).
Reaction SMILES: C([S:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][N:7]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=O)C.C[O-].[Na+].CO.I[CH2:38][C:39]([NH2:41])=[O:40]>CO>[Si:12]([O:11][C@H:9]1[CH2:8][N:7]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:6]([CH2:5][S:4][CH2:38][C:39](=[O:40])[NH2:41])[CH2:10]1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: NC(=O)CI
Reactant: CC(=O)SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a solution of (2S,4R)-2-acetylthiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.0 g) in methanol (20 ml) was added 28% sodium methoxide-methanol solution (0.98 ml) under an atmosphere of nitrogen at 0° C. After stirring at the same temperature for 10 minutes, to this reaction mixture was added 2-iodoacetamide (1.02 g) under the same condition. The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.11 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:17]([NH2:19])[CH3:18]>C1COCC1>[CH2:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[CH3:18]
Reactant: COc1cc2cc(C=O)c(Cl)nc2cc1F
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc2cc(F)c(OC)cc2cc1C=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a stirred solution of 2-chloro-7-fluoro-6-methoxyquinoline-3-carbaldehyde SMA 44034 (219 mg, 0.91 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added ethylamine (2 M in THF, 4.50 mL, 9.00 mmol) and the mixture was stirred at 150° C. for 2 h under microwave irradiation. After cooling to RT, the volatiles were removed under vacuum at 40° C. and the resulting yellow oil was taken up in a 2 N aq. HCl solution (15 mL) and stirred for 15 min at RT then neutralised with a 2 N aq. NaOH solution (15 mL). The mixture was extracted with CH2Cl2:MeOH=9:1 (50 mL) and the organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 2-(ethylamino)-7-fluoro-6-methoxyquinoline-3-carbaldehyde CCH 42068 as a yellow oil (105 mg, 46% yield).
Reaction SMILES: C=O.C(O)=O.[Br:6][C:7]1[CH:13]=[CH:12][C:10](N)=[C:9](C)[C:8]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[CH3:18][N:19]([CH3:20])[C:21]1[CH:12]=[CH:13][C:7]([Br:6])=[C:8]([N+:15]([O-:17])=[O:16])[C:9]=1[CH3:10]
Reactant: Cc1c(N)ccc(Br)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: C=O
Solvent: O=CO
Product: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.8 g of paraformaldehyde and 15 ml of formic acid are dissolved in 15 ml of DMF and heated to 90° C.-100° C. A solution of 18 g of 4-bromo-2-methyl-3-nitroaniline in 15 ml of DMF is added dropwise within 10 minutes. After 2 hours, the mixture is added to about 600 ml of ice water and the aqueous phase is extracted with 300 ml of ether. The organic phase is washed with Na2CO3 (1M), filtered and evaporated down. The product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (40/60). 15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is obtained as a brownish-orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([NH2:31])[CH:30]=1)[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=1)=[O:18])([CH3:12])[CH3:11].C([BH3-])#N.[Na+]>CO>[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([NH:31][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[CH:30]=1)[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=1)=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1cc(N)cc(C(=O)Nc2ncc(C(=O)O)s2)c1
Reactant: O=Cc1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(NCc2ccccc2Cl)cc(C(=O)Nc2ncc(C(=O)O)s2)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
2-Chlorobenzaldehyde (0.012 ml, 0.11 mM) was added to 2-[(3-isopropoxy-5-aminobenzoyl)amino]-5-thiazolecarboxylic acid (29 mg 0.09 mM) and 4A molecular sieves (90 mg) in methanol under an inert atmosphere at room temperature. After 1 hr sodium cyanoborohydride (7 mg, 0.11 mM) was added and the reaction mixture stirred for 16 hrs. The reaction mixture was filtered, concentrated in vacuo, the residue stirred with water then extracted with ethyl acetate (3×10 ml). The organic extracts were washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a pale yellow solid (22 mg, 55%); 1H nmr (d6-DMSO, δ values): 1.22 (6H, d); 4.36 (2H, m); 4.58 (1H, m); 6.24 (1H, s); 6.47 (1H, m); 6.84 (2H, m); 7.26 (3H, m); 7.37 (2H, m); 7.45 (1H, m); 7.76 (1H, br s). MS [M-CO2H]− 400, 402.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:22]=1)[C:20]#[N:21]>O1CCCC1>[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:22]=1)[C:20](=[NH:21])[NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: Cc1ccc(N)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=N)c2cncc(Br)c2)nc1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M, 5.14 mL, 0.0081 mol) was added slowly at a temperature of −78° C. over a period of 5 min to a solution of 5-methylpyridin-2-amine (0.738 g, 0.0068 mol) in anhydrous tetrahydrofuran (40 mL). The reaction temperature was raised to −40° C. and the reaction mixture was stirred for 15 min. It was cooled to −78° C. and 5-bromonicotinonitrile (1.25 g, 0.0068 mol) in tetrahydrofuran (5 mL) was added. The reaction temperature was raised to RT and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was used directly on the next step. MS (M+1): 292.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22]I>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[N:12]([CH3:22])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Reactant: CI
Product: Cc1ccc2c(=O)n3c4cc(C)c(C)cc4n(C)c3nc2c1

Procedure:
3,6,8,9-Tetramethylbenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and methyl iodide.
Reaction SMILES: [C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9]Cl)(=[O:3])[CH3:2].[I-:22].[Na+]>CC(C)=O>[C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9][I:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CCl)cc1C(OC(C)=O)OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(CI)cc1C(OC(C)=O)OC(C)=O
Yield: 91.1 %

Procedure:
3-(Diacetoxymethyl)-4-acetoxybenzyl chloride (987 g., 3.14 mole) and sodium iodide (494 g., 3.20 moles) in 3.5 liters acetone are refluxed for 6 hours. The reaction mixture is filtered, the filtrate is evaporated to dryness, triturated in ether and filtered to yield 1,162 g (91%) of 3-(diacetoxymethyl)-4-acetoxybenzyl iodide, m.p. 117°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1Br
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3-bromo-4-fluorobenzaldehyde and 20 ml of DMSO was added 0.49 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product extract with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.69 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 8.10-8.47 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(OCC)(=O)C>CCCCCC>[CH3:4][NH:6][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 40% aqueous solution of Methylamine hydrochloride (2.175 g, 33.2 mmol) and Triethyl amine (3.75 g, 37.18 mmol) at 0° C., added 4-Nitro-benzoyl chloride (4.6 g, 24.78 mmol) and stirred for 30 mins. The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The solid precipitate so obtained was filtered, washed with ice cold water and dried to afford 4 g (89%) of N-Methyl-4-nitro-benzamide. 1H NMR: (DMSO-d6): δ 8.78 (s, 1H), 8.32 (d, 2H), 8.06 (d, 2H), 2.8 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][CH:4]=1)[CH3:2].C(O[CH2:14][C:15]1[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[C:17]([CH3:30])[C:16]=1[CH2:31][CH3:32])(=O)C>>[CH2:23]([O:22][C:20]([C:18]1[NH:19][C:15]([CH2:14][C:4]2[NH:5][C:6]([CH2:14][C:15]3[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[C:17]([CH3:30])[C:16]=3[CH2:31][CH3:32])=[C:7]([CH2:8][CH3:9])[C:3]=2[CH2:1][CH3:2])=[C:16]([CH2:31][CH3:32])[C:17]=1[CH3:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1c[nH]cc1CC
Reactant: CCc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Product: CCc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C

Procedure:
condensing 3,4-diethylpyrrole with two molecular equivalents of benzyl 5-(acetoxymethyl)-4-ethyl-3-methylpyrrole-2-carboxylate to produce 2,5-bis(5-benzyloxycarbonyl-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(=O)c1sccc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2C(C)=O)cc1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
A flask was charged with 1-(3-bromothiophen-2-yl)ethanone (1.00 g, 4.88 mmol), 4-methoxyphenylboronic acid (0.740 g, 4.88 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dimethoxyethane (50 mL), and 2 N aqueous Na2CO3 (7.3 mL) and then warmed to 80° C. for 7 h. At that time the reaction mixture was poured into H2O and extracted with EtOAc. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography, eluting with 5-15% EtOAc/hexanes to afford the product (0.50 g, 2.2 mmol). MS (M+H)+ 233.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:27][O:28][C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>ClCCl>[CH3:27][O:28][C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:33]=1
Reactant: COC(=O)COc1cccc(N)c1
Reactant: COc1ccc(-c2oc3ncnc(Cl)c3c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(OC)cc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 400 mg (1.091 mmol) of 4-chloro-5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidine (for preparation see WO 03/018589) and 237.1 mg (1.309 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, add dichloromethane to the residue and purify by means of silica gel (eluent: dichloromethane/ethyl acetate 10:1). 139.3 mg (25% of theory) of the target compound are obtained as a light yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Na+].Cl[C:13]([F:18])([F:17])C([O-])=O.[OH-].[Na+].Cl>CN(C=O)C>[F:17][CH:13]([F:18])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Yield: 24 %

Procedure:
3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55° C. under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10% aqueous HCl followed by extraction with ethyl acetate (3×500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20% ethyl acetate/hexane gradient. 4-difluoromethoxy-3-hydroxybenzaldehyde was isolated in 24% yield (6.62 g). 1H NMR (CDCl3, 400 MHz) δ 6.1 (br s, 1H), 6.48-6.85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[OH-].[K+]>C(O)COCCO>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc([N+](=O)[O-])cc1Cc1ccccc1Cl

Procedure:
In the manner given in Preparation 11, 2-amino-2'-chloro-5-nitrobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(0-chlorobenzyl)-4-nitroaniline.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:20])[C:6]=2[CH:5]=[C:4]([CH3:21])[C:3]=1[CH3:22].N(S([O-])(=O)=O)(S([O-])(=O)=[O:26])[O].[K+].[K+]>CC(C)=O.OP([O-])(O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[O:9][C:10]3[C:2](=[O:1])[C:3]([CH3:22])=[C:4]([CH3:21])[C:5](=[O:26])[C:6]=3[C:7]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(Cc2oc3c(O)c(C)c(C)cc3c2C)cc1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3c(c2C)C(=O)C(C)=C(C)C3=O)cc1
Temperature: 45 °C

Procedure:
A solution of 7-hydroxy-2-(-4-methoxybenzyl)-3,5,6-trimethylbenzofuran from Step 4 (8.6 g, 29 mmol) in acetone (1.5 L) was added rapidly to a solution of potassium nitrosodisulfonate (Fremy's salt) (25 g, 93 mmol) in 0.055 M KH2PO4 buffer (1.5 L) at room temperature. The reaction was slowly heated to 45° C. over a period of 2 hr. The reaction was then cooled and the quinone was extracted with EtOAc (2x, 500 mL). Evaporation of the organic solvent gave a solid residue which was crystallized and re-crystallized from EtOH, to give the title compound, mp 111°-113° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-4-trifluoromethylbenzamide was prepared from p-trifluoromethylbenzoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 44 mg, 83 μmol, 73%). LC/ESI-MS: m/z=526 [M+H]+; m/z=524 [M−H]−; Rt=3.67 min.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:23]2[CH2:24][CH2:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: O=C1CCc2ccccc2C1
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2ccccc2C1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (350 mg, 1.4 mmol) and 2-tetralone (318 mg, 2.2 mmol)in 20 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (462 mg, 2.2 mmol) and stirred at room temperature overnight. The mixture was concentrated and eluted through SPEC SCX cartridge and concentrated to dryness. The residue was purified by silica gel column chromatography to give 2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a solid, LC-MS, RT=1.9 min, M+1=372.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[CH:5]=[C:4]([C:14]#[N:15])[N:3]=1.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.CCN(CC)CC>CN1C(=O)CCC1>[C:14]([C:4]1[N:3]=[C:2]([NH:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])#[N:15]
Reactant: COc1cccc2cc(C#N)nc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cccc2cc(C#N)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 130 °C
Yield: 98.2 %

Procedure:
To a solution of 1-chloro-8-methoxyisoquinoline-3-carbonitrile (230 mg, 1.05 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (294 mg, 1.57 mmol) and Et3N (212 mg, 2.1 mmol). The reaction mixture was heated to 130° C. for 45 minutes in a microwave reactor and was subsequently quenched with H2O (20 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:20-1:2 gradient) to give the title compound (380 mg, 2 batches, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.25 (s, 1H), 6.97 (d, 1H, J=8.0 Hz), 4.60-4.80 (m, 1H), 4.01 (s, 3H), 3.78-3.79 (m, 1H), 3.27-3.57 (m, 3H), 2.29-2.34 (m, 1H), 1.94-1.99 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.BrBr.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][C:16]=1[OH:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:17][C:16]=1[O:31][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Reactant: CC(=O)Cc1ccc(F)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Fluorophenylacetone (388 μl, 2.9 mmol) in DCM (12 ml) was cooled to 0° C. and bromine (672 mg, 2.9 mmol) was slowly added. The mixture was stirred for 30 min and then concentrated in vacuo. The crude intermediate was added to a mixture of 6-chloro-1-(4-fluorophenyl)-1H-indazol-5-ol, (99c) (762 mg, 2.9 mmol) and potassium carbonate (804 mg, 5.8 mmol) in THF (12 ml). The mixture was stirred for 4 h, filtrated and concentrated. The crude product was purified by flash chromatography (EtOAc/heptane, product eluted at 40% EtOAc) to give the title compound (1.06 g, 88%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][NH:16][CH2:15][CH2:14]1>>[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Product: Cc1cc2nc(N3CCSc4ccccc4C3)nc(NCCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine and propane-1,3-diamne, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI+) [(M+H)+] 386, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.61-7.71 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.15-7.23 (m, 1H), 7.08-7.15 (m, 1H), 6.80 (s, 1H), 5.00 (s, 2H), 4.41 (br. s., 2H), 3.75 (d, J=4.0 Hz, 2H), 2.89-2.98 (m, 4H), 2.53 (s, 3H), 1.84 (m, 2H).