Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[C:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: N#CCC(=O)NCc1ccccc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)n(Cc2ccccc2Cl)c(=O)c1C#N
Yield: 87 %

Procedure:
A solution of N-(2'-chlorobenzyl)-2-cyanoacetamide 179 g. (0.86 mole) and 2,4-pentanedione 86 g. (0.86 mole) in 500 ml. of 95% ethanol containing 10 ml. of piperidine is refluxed for 24 hours, after cooling the white crystalline product is isolated by vacuum filtration washed with ether and dried in vacuo to give 237.3 g. (87% yield) mp>250° C.;ν2210 (CN) and 1650 cm.-1 (C= O).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH:20]12[CH2:27][NH:26][CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2>CS(C)=O>[CH:20]12[CH2:27][N:26]([C:3]3[C:2]([Cl:1])=[C:11]4[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]4[CH:12]4[CH2:14][CH2:13]4)=[CH:5][CH:4]=3)[CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2
Reactant: C1CC2CNCC2N1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCNC4C3)ccc2c1=O

Procedure:
650 mg (2.3 mmol) of 8-chloro-l-cyclopropyl-7-fluoro-1,4 -dihydro-4 -oxo-3 -quinolinecarboxylic acid together with 315 mg (2.8 retool) of 2,7-diazabicyclo[3.3.0]octane and 510 mg (4.6 mmol) of 1,4-diazabicyclo[2.2.21]octane are heated for six hours at 120° C. in 23 ml of dimethyl sulphoxide. All volatile components are removed under a high vacuum, and the residue is stirred thoroughly with acetonitrile and dried at approximately 100° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH2:26]([N:28]([CH2:49][CH3:50])[CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>ClCCl>[CH2:49]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)[C:23](=[O:25])[CH2:22][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:21])[CH:20]=[C:11]1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:50]
Reactant: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-acetic acid (Int. E2) (0.26 g, 1 equiv), N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int. A2) (0.265 g, 1 equiv), HATU (0.28 g, 1.2 equiv) and diisopropylamine (0.32 ml, 2.4 equiv) in dichloromethane (15 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated, and the product purified by column chromatography (silica, 2% [2M ammonia in methanol] in dichloromethane). Product fractions were evaporated to an off-white foam (0.201 g). Trituration with ether gave the title compound as a white solid (0.476 g). 1H-NMR (d6-DMSO, ca 2:1 rotamer mixture) δ 0.93 (6H, 2×t), 2.38–2.80 (4H, m), 2.90–3.05 (4H, m), 3.45 (2H, m), 4.30–4.95 (4H, m), 5.23–5.58 (2H, m), 6.06 (1H, 2×s), 7.14–7.38 (7H, m), 7.50–7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found (M+1)=676. C39H38F5N3O2 requires 675.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:26])[CH2:3]1
Reactant: CC(C)NC(=O)c1ccc(F)cc1[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(F)cc1[C@H]1CC(F)(F)CN1
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 4,4-difluoro-2-(5-fluoro-2-(isopropylcarbamoyl)phenyl)pyrrolidine-1-carboxylate (I-50) (203 mg, 0.525 mmol) in DCM (0.4 mL) was added TFA (1 mL). After stirring for 2 hours the mixture was concentrated to dryness, diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over sodium sulfate and concentrated to dryness to give (R)-2-(4,4-difluoropyrrolidin-2-yl)-4-fluoro-N-isopropylbenzamide (I-51) as a pale brown solid. MS m/z 287.1 (M+H)+. 1-51 was also isolated as a racemic mixture using un-resolved 1-45A and 1-45B from Method A in the above sequence.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[CH:12][C:11]=1[OH:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]([O-:43])=[O:42].[Na+]>C(O)(=O)C.CN(C)C=O.O>[N+:41]([C:12]1[C:13]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[C:14]([Cl:16])[CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]=1[OH:40])([O-:43])=[O:42]
Reactant: O=N[O-]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
In 100 ml of acetic acid and 100 ml of dimethylformamide was dissolved 20 g (35×10-3 mole) of 2-benzamido-4-chloro-5-{2-(2,4-di-t-amylphenoxy)butanamido}phenol. To the solution was added dropwise slowly a solution of 2.7 g of sodium nitrite dissolved in 5 ml of a distilled water at room temperature, and then the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold water, and precipitated yellow solids were collected by filtration and washed with water. Yield: 21 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC)=O)(C6C=CC=CC=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63]([O:67]C(N1CCCC1C(O)=O)=O)(C)(C)[CH3:64].[CH3:78][N:79]([CH:81]([C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[C:82]([OH:84])=O)[CH3:80].COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([O:67][CH2:63][CH3:64])[CH2:44][N:43]6[C:82](=[O:84])[CH:81]([N:79]([CH3:78])[CH3:80])[C:85]6[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: CN(C)C(C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: CCOC1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(c2ccccc2)N(C)C)C1

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-ethoxy-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Dimethylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C49H56N8O5: 836.44 (M+); Found: 837.80 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:14])=[O:13]
Reactant: Sc1cccs1
Reactant: O=C1CCCCCO1
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with ε-caprolactone to obtain 6-(2-thienylsulfanyl) hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C=CC(=O)O)cc(OC)c1OC
Yield: 88 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (5.0 g, 0.025 mol), malonic acid (5.30 g, 0.050 mol), piperidine (4–8 mL) and acetic acid (25–35 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside a microwave oven and irradiated for 4–8 minutes in parts. The cooled mixture was poured into ice cold water and then acidified with 5% HCl. The precipitated yellow solid was filtered and recrystallized with aq. ethanol to afford 3,4,5-trimethoxycinnamic acid in 88% yield; mp 127° C. (lit mp 126–128° C.) whose spectral data was found similar to the reported values 1H NMR (CDCl3) δ 7.73 (1H, d, J=16.0 Hz, —CH═CH—COOH), 6.78 (2H, s, H-2 & H-6), 6.38 (1H, d, J=16.0 Hz, CH═CH—COOH), 3.91 (9H, s, 3-OCH3, 4-OCH3 & 5-OCH3); 13C NMR: δ 172.6 (COOH), 153.8 (C-3 and C-5), 147.4 (C-4), 140.8 (CH═CH—COOH), 129.8 (C-1), 116.8 (CH═CH—COOH), 105.8 (C-2 and C-6), 61.4 (4-OCH3), 56.5 (3-OCH3 and 5-OCH3).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.[CH3:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>C(#N)C.N1CCCC1C(O)=O>[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH:15]([CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:28]2[C:27]3[C:31](=[C:23]([CH2:22][S:21][CH3:20])[CH:24]=[CH:25][CH:26]=3)[NH:30][CH:29]=2)[C:13](=[O:14])[O:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: Cc1ccc(C=O)cc1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(C)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
1.28 g (10.7 mmol) of 4-methylbenzaldehyde, 1.54 g (10.7 mmol) of Meldrum's acid and 58.0 mg (0.51 mmol) of D,L-proline were added to a solution of 2.00 g (10.2 mmol) of the compound from Example 8A in 80 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 4.34 g of the title compound were obtained and were reacted without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[N:27]=[C:28](Br)[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]2[N:27]=[C:28]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:10][CH2:9]3)[S:29][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: OC1CCN(C2CCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Yield: 56.5 %

Procedure:
1-Cyclobutyl-piperidin-4-ol (1.6 grams, 10 mmol) in tetrahydrofuran (20 mL) was treated with cooled and stirred suspension of sodium hydride (0.9 grams, 18 mmol) in tetrahydrofuran (20 mL) slowly over a period of 30 minutes; the reaction mixture was stirred for 1 hour. A solution of 2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (3 grams, 9 mmol, obtained in preparation 1) in tetrahydrofuran (30 mL) was added drop wise over a period of 15 minutes and refluxed the reaction for 6 hours. Reaction mass was quenched with ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (ethylacetate/n-hexane, 1/1) to obtain the title compound (2.0 grams).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]>>[CH2:18]([C:20]1([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][C:2]2[CH:9]=[C:8]([CH:10]([OH:17])[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reactant: N#Cc1ccc(C(O)c2cccnc2)cc1F
Product: CCC1(c2cccc(Oc3cc(C(O)c4cccnc4)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
Using the procedure described in Example 2, the crude title compound was prepared starting with 2-fluoro-4-(hydroxy-pyridin-3-yl-methyl)-benzonitrile (as described in Step C above) (0.075 g, 0.329 mmol) and 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.082 g, 0.329 mmol). Purification by preparative HPLC and conversion to the free base yielded the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.CCCCCCC>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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Br)ccc3c2CC1
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: COCCOC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Yield: 36.2 %

Procedure:
A mixture of 3-benzoyl-8-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.48 g, 4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.46 g, 0.40 mmol) in dimethoxyethane (10.0 mL) and a solution of phenylboronic acid (0.60 g, 4.80 mmol) in dimethoxyethane (10.0 mL) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1 to give a brown foam. Column chromatography (silica gel, 20-50% EtOAc/heptane) afforded 0.53 g (36%) of the title compound as a solid: mp 213-232° C.; 1H NMR (400 MHz, CDCl3) δ 8.13, 7.61, 7.44-7.40, 7.34-7.29, 4.07-3.98, 3.70-3.63, 3.21-3.13, 2.92-2.83; 13C NMR (100 MHz, CDCl3) δ 171.7, 142.3, 137.0, 135.9, 135.3, 134.9, 129.3, 128.7, 128.6, 128.3, 127.3, 126.5, 126.4, 119.3, 117.7, 110.3, 109.0, 51.4, 45.8, 29.1, 26.2; IR (drift) 3262, 1602, 1466, 1432, 1323, 1291, 1243, 811, 781, 763, 751, 743, 707, 699, 627 cm−1; MS (EI) m/z 366 (M+); HRMS (FAB) calcd for C25H22N2O+H: 367.1810, found: 367.1813; Anal. Calcd for C25H22N2O: C, 81.94; H, 6.05; N, 7.64. Found: C, 81.43; H, 6.20; N, 7.42.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[CH:40]([CH3:42])[CH3:39])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4C(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)-phenyl)pyrrolidine-2-carboxamide [Example 69(b)] was reacted with acetone under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 585 (M+1).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[N:11]([C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:24][C:25]=1[F:30]
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)cn(C)c1=O)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)c(F)c2)N(c2cc(Cl)cn(C)c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-6-(4-chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BA) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. tR: 1.15 min (HPLC 3); ESI-MS: tR=1.13 min, [M+H]+ 572/574/576 (LC-MS 1); TLC: Rf=0.25 (EtOAc).
Reaction SMILES: O[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][S:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([CH3:27])[CH:19]=1.Cl.N1C=CC=CC=1>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][S:14][C:8]4=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[C:20]([CH3:27])[CH:19]=1
Reactant: N#Cc1cnc2cc3scnc3cc2c1O
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2c(C#N)cnc3cc4scnc4cc23)c(C)cc1Cl
Yield: 15.5 %

Procedure:
To a mixture of 100 mg (0.44 mmol) of 8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile in 5 mL of phosphoryl chloride is added five drops of N,N-dimethylformamide. The mixture is heated at reflux temperature for 30 minutes and then concentrated in vacuo. To the residue at 0° C. is added 50 mL of water. The solids are collected, washed with water, and dried in vacuo. To a mixture of this compound in 2 mL of 2-ethoxyethanol are added 76 mg (0.44 mmol) of 4-chloro-5-methoxy-2-methylaniline and 20 mg of pyridine hydrochloride. The mixture is refluxed for one hour and concentrated. The residue is chromatographed by silica gel chromatography, eluting with 9:1 methylene chloride/methanol to yield 26 mg (16%) of product as a dark oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C1CCCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: C1CCCCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in cyclohexane were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in cyclohexane at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42]
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.