Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].C(N(C(C)C)CC)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39].C(OCC)(=O)C>O1CCCC1>[Br:36][CH2:37][C:38]([NH:1][CH:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:39]
Reactant: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CBr
Reaction time: 2 h

Procedure:
To a stirring solution of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. was added diisopropylethylamine (4.1 ml, 23.537 mmoles) and bromoacetyl bromide (2.05 ml, 23.530 mmoles). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl>CC#N>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][NH:16][C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[CH:3]=[O:2])[CH:15]=[CH:14][N:13]=2)=[CH:24][CH:23]=1
Reactant: COC(OC)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Agent: Cl
Solvent: CC#N
Product: O=Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 27 (2.2 g) was treated with 30 mL of 3N HCl in 60 mL of CH3CN at room temperature overnight. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate/sat. NaHCO3. Yield: 1.9 g, 99%. LC-MS showed the product had the expected M+H+ of 320.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2cc[nH]c(=O)c2c1
Product: Cc1ccc2ccnc(Cl)c2c1
Temperature: 25 °C

Procedure:
7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in phosphorus oxychloride (30 mL) is heated to reflux for 13 hours. The mixture is cooled to room temperature, then concentrated to a smaller volume. The residue is diluted with ice water and the pH is adjusted to ca. 8 by slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4×20 mL) and the combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The resulting dark oil is purified by column chromatography eluting with 25% EtOAc/hexanes to give the product (1.6 g, 9 mmol) as a light yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>>[CH3:26][O:27][CH2:28][C:29]([NH:25][C:23]1[CH:22]=[CH:21][C:20]2[N:16]([C:14]3[CH:13]=[N:12][CH:11]=[C:10]([NH:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[N:15]=3)[CH:17]=[N:18][C:19]=2[CH:24]=1)=[O:30]
Reactant: COCC(=O)Cl
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Product: COCC(=O)Nc1ccc2c(c1)ncn2-c1cncc(N[C@@H](C)c2ccccc2)n1
Yield: 49.7 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and methoxyacetyl chloride (12 mg, 0.11 mmol) furnished the product (20 mg, 50%) after chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.Cl.[C:27]([S:46][CH2:47][CH2:48][NH2:49])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH:49][CH2:48][CH2:47][S:46][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:16])=[CH:11]2
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a mixture of 7-[(2-methoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.46 g), 2-(tritylthio)ethylamine hydrochloride (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g), triethylamine (0.20 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.28 g) at 0° C., and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.90 g, quantitative) as colorless crystals. melting point 65-66° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@@H:8]([OH:16])[CH2:7]1)=[O:4].[CH2:19](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[C:10]([CH3:19])[CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@H:8]([OH:16])[CH2:7]1)=[O:4]
Reactant: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Product: Cc1cc(C)c2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@H]2O
Yield: 85 %

Procedure:
Step BM (2): The crude product from Step BM (1) was reduced with L-selectride by following a procedure analogous to Step BJ (1) to afford 6.5 g (85% yield) of trans-2,2,2-trifluoro-N-(3-hydroxy-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)acetamide (6.5 g, 85% yield). LC-MS (M+H)+=274.10 1H NMR (500 MHz, CDCl3) δ ppm 7.32 (d, 1H) 6.98-7.03 (m, 1H) 6.93-6.97 (m, 1H) 5.22 (t, 1H) 5.12 (d, 1H) 2.81-2.98 (m, 1H) 2.64-2.74 (m, 1H) 2.32-2.37 (m, 3H) 2.27-2.32 (m, 3H) 1.94 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:35])([CH3:34])[C:10]([NH:12][C@H:13]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:35])([CH3:34])[C:10]([NH:12][C@H:13]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 102.1 %

Procedure:
The benzyl ester (0.82 g, 1.71 mmol) obtained in Step C and 10% palladium on carbon (150 mg) were stirred together in ethyl acetate (5 mL). The solution was degassed and a hydrogen atmosphere introduced over the reactants using a balloon for 32 hours. The reaction products were isolated by filtering the reaction mixture through a Celite plug. The plug was washed with additional ethyl acetate (3×10 mL). The combined filtrates were evaporated under vacuum to afford the product (680 mg, 102%). 1H NMR (400 MHz, CDCl3): 1.30 (s, 9H), 1.41 (s, 6H), 3.32 (dd, 1H), 3.42 (m, 1H), 4.87 (br s, 1H), 6.82 (d, 1H), 7.13-7.35 (m, 8H), 7.60 (d, 1H), 8.28 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[C:27]=O.ClS(Cl)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([C:27]#[N:26])=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=C=O
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g, 5.8 mmol) in THF (anhydrous, 50 mL) at −78° C. was added chlorosulfone isocyanate (0.66 mL, 6.7 mmol). After 90 min, DMF (9 mL, 116 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.1 g, 52%) as a white powder, mp 165-167° C. 1H NMR (d6-DMSO, 300 MHz) δ1.36 (s, 9H), 1.61 (s, 6 H), 6.44 (d, 1 H, J=3.7 Hz), 6.92 (d, 1 H, J=8.2 Hz), 7.27-7.32 (m, 2 H), 7.36 (‘d’, 1 H, J=1.5 Hz), 10.36 (s, 1 H). MS (EI) m/z 367 [M]+.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]5[CH2:26][CH2:27][CH2:28][CH2:29][O:24]5)[CH:37]=4)[CH:23]=[CH:22][C:5]=3[C:6]=2[N:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOC4CCCCO4)c3)ccc1-2

Procedure:
8-Bromo-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole were reacted under Suzuki conditions to give 2-(1-Isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. LCMS: RT=4.56 min, [M+H]+=506
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=1>>[NH2:15][C:13]1[N:12]=[C:11]([NH:16][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:10]=[C:9]([Cl:8])[N:14]=1
Reactant: CCCCN=C=O
Reactant: Nc1cc(Cl)nc(N)n1
Product: CCCCNC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 80 °C

Procedure:
8.6 cm3 butylisocyanate was added to a suspension of 5 g 6-chloro-2,4-diaminopyrimidine in 50 cm3DMSO. The reaction medium was maintained at 80° C. until it was shown by TLC that the starting compound had disappeared.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Clc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCC5)cc4ccc3n12

Procedure:
A mixture of 1.0 g. of 3-chloroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.0 ml. of pyrrolidine and 5 ml. of N-methyl-2-pyrrolidinone is stirred and heated at reflux for 17 hours, cooled and diluted with 100 ml. of ethyl acetate. The precipitate of 3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, stirred with 50 ml. of 1% aqueous triethylamine hydroiodide and recollected; m.p. 312°-320° C. after crystallization from methanol.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2nc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (103 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (72.1 mg, 74%) as a pale-brown solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH2:17][C:18](=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)C>[CH2:19]([CH:18]1[CH2:17][C:11]2[C:10](=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:16])[CH2:9][NH:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cl)c1CC(=O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc2c1CC(Cc1ccccc1)NC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
427 mg of 1-[2-(tert-butoxycarbonylaminomethyl)-6-chlorophenyl]-3-phenyl-2-propanone was dissolved in 5 mL of methylene chloride, and 3 mL of trifluoroacetic acid was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. After confirming the loss of the starting material, it was concentrated under reduced pressure, and the residue obtained was dissolved in 5 mL of ethanol. 173 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was recrystallized using chloroform hexane to obtain 173 mg of a title compound as a white crystal. Further, a mother liquor upon recrystallization operation was purified using PLC (chloroform:methanol=20:1) to obtain 88.6 mg of a title compound as a pale yellow oily substance. In total, 262 mg (yield 89%) of a title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:12](F)=[N:13][CH:14]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[C:12]([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:13][CH:14]=1
Reactant: C[C@H](O)C(F)(F)F
Reactant: Fc1ncc(Cl)cc1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: C[C@H](Oc1ncc(Cl)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a mixture of 1.133 g (S)-1,1,1-trifluor-2-propanol in 10 ml dry DMF 397 mg sodium hydride (60%) was added and the mixture was stirred at room temperature for 30 minutes. The resulting solution was added dropwise at RT to a solution of 2.185 g 5-chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine in 20 ml dry DMF. The reaction mixture was then stirred at room temperature for 2 h. The resulting light yellow mixture was partitioned between water and ethyl acetate, the phases were separated. The organic phase was dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate=9:1 to yield 2.330 g (76.80%) of the title compound as colorless liquid, 336.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH:17]([N:21]([CH2:26][CH2:27][CH3:28])[C:22](=O)[CH2:23][CH3:24])[CH2:18]2)=[CH:14][CH:13]=1.[OH-].[Na+]>C1COCC1>[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH:17]([N:21]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])[CH2:18]2)=[CH:14][CH:13]=1
Reactant: CCCN(C(=O)CC)C1Cc2ccc(Br)cc2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2ccc(Br)cc2C1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Lithium aluminium hydride (90 mg, 2.36 mmol) and aluminium chloride (350 mg, 2.25 mmol) were added to dry THF (25 mL). The mixture was cooled to -15° C. and kept at this temperature for 15 min. N-(6-Bromo-indan-2-yl)-N-propyl-propionamide (preparation 14, 0.35 g, 1.13 mmol) dissolved in dry THF (10 mL) was added and the reaction mixture was stirred at -15° C. for 90 min. Aqueous NaOH (15 mL, 15%) was added and the mixture extracted with ethyl acetate. The layers were separated and the organic layer washed with water, dried (Na2CO3) and the solvent was evaporated to dryness. The crude product was chromatographed and the pure fractions were pooled, yielding 280 mg (83%) of (6-bromo-indan-2-yl)-dipropyl-amine as the free base. The amine was converted to its hydrochloride salt with EtOH-HCl and recrystallized from a mixture of 2-propanol and isopropyl ether. m.p. 196°-198° C. (HCl); 1H NMR (300 MHz, CDCl3) δ 0.90 (t, 6H), 1.50 (m, 4H), 2.50 (t, 4H), 2.75-3.08 (m, 4H), 3.60-3.75 (p, 1H), 7.05 (d, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.32 (s, 1H); 13C NMR (75.4 MHz, CDCl3) δ 12.02, 20.30, 36.25, 36.62, 53.39, 63.25, 119.82, 125.95, 127.56, 129.26, 141.00, 144.47; MS m/e 295 (6, M+), 269 (100), 266 (98), 116 (54), 115 (41).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=[CH:8]1.ClC1C(C(OO)=[O:33])=CC=CC=1>ClCCl>[NH:7]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][S:15]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:33])[N:9]=[CH:8]1
Reactant: O=C(OO)c1ccccc1Cl
Reactant: c1ccc(CCCSCCCc2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(CCCc1ccccc1)CCCc1c[nH]cn1
Reaction time: 0.5 h

Procedure:
0.5 g of potassium carbonate in 40 ml of dichloromethane are added to 2 mmol of the compound obtained in Example 46 and the mixture is stirred for 30 min. 2.5 mmol of chloroperbenzoic acid in 20 ml of dichloromethane are slowly added to the suspension and the mixture is stirred for 2 h at room temperature. The suspension is filtered and purification is carried out by chromatography. The title compound is recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH:8]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[CH3:21][O:15][C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: O=C1CCCCC(C=Cc2cccs2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCc2cccs2)CCCC1

Procedure:
The product of Example 173 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]1=[O:26].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[C:27]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][CH:7]=2)[C:15](=[O:26])[CH:16]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccc(OC)cc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 13.9 g of the product of Step C, 8.2 ml of triethylamine and 4.5 ml of benzoyl chloride were reacted to obtain 18 g of the expected product.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([Cl:50])=[C:29]([C:46]([CH3:49])=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:28]1[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[N:36]=2)=[C:46]([CH3:49])[CH:47]=[CH:48][C:27]=1[NH:26][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 49.5 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (95 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.63 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 51%) was obtained as a white powder.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:16])=O.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(O)ccnc2c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)ccnc2c1
Temperature: 0 °C

Procedure:
22.74 g of 4-hydroxy-7-methoxyquinoline are added to 200 g of phosphorus oxybromide preheated to a temperature in the region of 110° C. The reaction medium is heated at this same temperature for 3 hours. The reaction medium is poured, while hot, into a mixture of 500 ml of EtOAc and 500 ml of ice-cold water. The medium is neutralized with potassium carbonate to pH 7. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, evaporated under reduced pressure and then purified by column chromatography (SiO2, EtOAc/cyclohexane 50/50 by volume as eluents, Ar), and 14.6 g of the expected product are obtained.