Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4].[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28](O)=[O:29]>CN(C=O)C.CC(O)=O>[N:22]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16])=[O:6])[CH3:4])=[O:29]
Reactant: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Yield: 54.9 %

Procedure:
After 2.31 g (5.0 mmols) of HCl.H-Ala-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 18.4 g (54.9%) of Z-pyroGlu-Ala-Arg(NO2)-CHA.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[CH2:8]O.[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:8][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5][C:6]=1[CH3:10]
Reactant: BrP(Br)Br
Reactant: Cc1cncc(C)c1CO
Solvent: ClCCl
Product: Cc1cncc(C)c1CBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3,5-dimethylpyridin-4-yl)methanol (2.55 g, 18.6 mmol) in anhydrous dichloromethane (130 mL) was added tribromophosphane (2.0 mL, 21.1 mmol). The mixture was stirred at room temperature for 5 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 4-(bromomethyl)-3,5-dimethylpyridine. The crude product was used without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:25][CH3:26]>C1COCC1>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:3]([C:1]#[N:2])([CH2:25][CH3:26])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
In a 100 mL 2-neck round-bottomed flask, tert-butyl 3-cyanoazetidine-1-carboxylate (0.80 g, 4.4 mmol) was dissolved in THF (16 mL). The colorless solution was cooled to −76° C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 4.8 mL, 4.8 mmol) was added dropwise over 20 min. The yellow solution was stirred at −76° C. for 30 min then iodoethane (0.50 mL, 6.2 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 30 min and then warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ˜100 ml EtOAc (2×). The combined organic layers were washed with ˜10 mL water and ˜10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to afford 0.84 g (91%) of 3-cyano-3-ethyl-azetidine-1-carboxylic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:11]([N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:11]([N:18]1[C:31]2[C:26](=[CH:27][C:28]([CH2:2][CH:3]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:29][CH:30]=2)[C:20]2([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCC1CCCCCCC1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)c2ccc(CC3CCCCCCC3)cc2C12CCNCC2
Temperature: 55 °C
Reaction time: 18 h

Procedure:
1-Bromomethyl-cyclooctane (0.087 g, 0.424 mmol) and 1-benzyl-spiro[indoline-3,4′-piperidin]-2-one (0.030 g, 0.141 mmol) were dissolved in dry N,N-dimethylformamide (3 mL). Potassium carbonate (0.078 g, 0.565 mmol) and a catalytic amount of potassium iodide were added. The reaction mixture was then stirred at 55° C. under nitrogen atmosphere for 18 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (50% ethyl acetate/hexanes) to yield the title compound as an oil.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.Br[CH2:34][CH2:35][OH:36]>CN(C=O)C>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:34][CH2:35][OH:36])[CH2:19][CH2:20]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: OCCBr
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CCO)CC3)c(F)c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (0.3 g), triethylamine (0.2 g), 2-bromoethanol (0.15 g), and DMF (5 ml) was heated with stirring at 90° C. for 3 hours. After the solvent evaporated, the residue was dissolved in 2N sodium hydroxide solution, neutralized with aqueous acetic acid, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (0.08 g), mp 225°-228° C.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([C:20](O)=[O:21])#[C:16][C:17]([OH:19])=[O:18]>>[CH2:10]([N:9]1[C:20](=[O:21])[C:15](=[CH:16][C:17]([OH:19])=[O:18])[S:8][C:7]1=[N:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCNC(=S)NCCCCC
Product: CCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCC
Yield: 44 %

Procedure:
Prepared by the method described in Example 1 from N,N'-dipentylthiourea (31.4 g, 150 mmoles) and acetylenedicarboxylic acid (17.1 g, 150 mmoles). Recrystallization from acetonitrile gave the product (20.6 g), mp 85°-88° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1.[OH-].[K+]>C(O)CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(OC)cc(Br)c3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1cc(Br)c2oc(C3CCNCC3)cc2c1
Reaction time: 18 h

Procedure:
7.6 g of 4-(7-bromo-5-methoxy-benzofuran-2-yl)-1-ethoxycarbonyl-piperidine are dissolved in 80 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the resulting cloudy solution is heated at 160° with vigorous stirring for 18 hours. The reaction mixture is cooled to 100°, diluted with 80 ml of toluene, and cooled further to 20°. The reaction solution is extracted twice with 1000 ml of water each time and then four times with 200 ml of a 10% solution of methanesulfonic acid in water each time. The resulting solution in methanesulfonic acid is adjusted to pH 12 by the addition of 30% sodium hydroxide solution and extracted by shaking with 1000 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and concentrated by evaporation. Crystallisation from ethyl acetate yields 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidine having a melting point of 149°-152°. There is obtained from the base by treatment with methanolic hydrochloric acid and recrystallisation from methanol/ether 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidine-hydrochloride having a melting point of 242°-243°.
Reaction SMILES: C([O-])(=O)C.[Na+].CCO[C:9]([CH:11]1[C:15](=O)[CH2:14][CH2:13][CH2:12]1)=[O:10].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[C:19]1([C:18]2[NH:26][C:9](=[O:10])[C:11]3[CH2:12][CH2:13][CH2:14][C:15]=3[N:25]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1[nH]c(-c2ccccc2)nc2c1CCC2
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of 15.6 g (190 mmol) of sodium acetate, 25 mL (172.7 mmol) of ethyl cyclopentanone-2-carboxylate, 27.7 g (177 mmol) of benzamidine hydrochloride and 250 mL of xylene was refluxed with a Dean Stark trap for 8 hours. Most of the xylene was distilled off and the hot reaction mixture was poured onto crushed ice. The reaction mixture was left to stand at room temperature for 0.5 hour, then vacuum filtered to remove the product, as a gray solid. The solid was air dried overnight to yield 13.35 g (37.0%) of 2-phenyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one. 1H-NMR (CDCl3) δ2.11 (2H,m), 2.90 (4H,m), 7.5 (3H,m), 8.18 (2H,m).
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH2:13][CH2:14][CH:15]=2)[N:10]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C2(CCOCC2)C2=CCCC=C21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate from Step B (55.0 mg, 0.173 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:23])[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[NH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([CH2:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:11](=[O:23])[CH2:12][CH2:13]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
1-(3-morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.244 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (76 uL, 2.44 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed and the bed washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 64 mg of yellow oil (90%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.71 (t, J=4.5 Hz, 4H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.44-2.36 (m, 6H) 1.83-1.65 (m, 2H). MS (ESI): 290.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[O:30][CH3:31])=[O:32])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=1
Reactant: COc1cc(F)ccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)ccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Yield: 132.7 %

Procedure:
The compound of Example 175 (70 mg) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred for 2 hours at room temperature and evaporated to give the title compound (72 mg) as the trifluoroacetic acid salt.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1CCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2CCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.86-2.95 (4H, m), 5.03 (2H, s), 5.70 (1H, d, J=2.0 Hz), 6.91-7.01 (4H, m), 7.21-7.24 (2H, m), 7.33-7.36 (2H, m), 7.58 (1H, d, J=1.6 Hz), 7.96 (1H, s), 8.57 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C24H18ClFN4O, 433; Found, 433.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]3=[O:21])[C:10]=2[CH:11]=1.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)OC2)C1=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:43][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:37])[C:13]3=[O:21])[C:10]=2[CH:11]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COCCOc1ccc2c(c1)C1(CO2)C(=O)Nc2ccccc21
Product: COCCOCCN1C(=O)C2(COc3ccc(OCCOC)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 5-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6) δ7.31-7.27 (m, 1H), 7.15-7.10 (m, 1H), 7.06-6.99 (m, 2H), 6.63-6.58 (m, 1H), 6.56-6.53 (m, 1H), 6.42-6.36 (m, 1H), 4.81 (ABq, 2H), 4.11-4.02 (m, 2H), 3.83-3.76 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.54 (m, 4H), 3.52-3.45 (m, 2H), 3.43 (s, 3H), 3.33 (s, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[OH2:9]>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:3]([OH:9])=[CH:2][C:8]([CH3:7])=[N:5]2)=[CH:7][CH:8]=1
Reactant: O
Reactant: Nc1cccc(F)c1
Agent: Cl
Product: Cc1cc(O)c2ccc(F)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-fluoroaniline (4.44 g, 40 mmol) and acetoacetic ester (5.20 g, 40 mmol), a catalytic amount (2 drops) of dilute hydrochloric acid was added at 25° C., within 10 minutes water began to separate and small amount of heat was generated. The reaction mixture was allowed to stand at 25° C. overnight; the reaction mixture was diluted with dichloromethane (150 mL), washed successively with 0.5 N HCl (2×50 mL), 0.5 N NaOH (2×50 mL) and water, dried over anhydrous sodium sulphate. Dichloromethane was evaporated and oily residue was added to the refluxing diphenyl ether (40 mL) over a period of 5 minutes, refluxing was continued for 1 hour after that reaction mixture was cooled at 25° C. and solid was separated by filtration, washed with diethyl ether to remove some coloring impurities. The product was obtained as yellow solid (2.3388 g, 33%, based on 3-fluoroaniline) as isomeric mixture of 5 and 7-fluoro-2-methylquinolin-4-ol, used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]([F:10])([F:9])[F:8])[CH3:2].O.[F:32][C:33]([F:37])([F:36])[CH:34]=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:6][C:7]([F:8])([F:9])[F:10])=[CH:34][C:33]([F:37])([F:36])[F:32])[CH3:2]
Reactant: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC(F)(F)F)CC(F)(F)F
Temperature: 100 °C
Yield: 86 %

Procedure:
To a solution of 4,4,4-trifluoro-2-(triphenyl-λ5-phosphanylidene)-butyric acid ethyl ester (2.0 g, 4.65 mmol) in THF (5 mL) was added 1 mL of trifluoroacetaldehyde hydrate (tech.). The mixture was sealed in a pressure tube and heated at 100° C. for 3.5 h. After cooling to 23° C., the reaction mixture was eluted through a pad of silica gel (100 g) and Na2SO4 with Et2O (100 mL) to remove the by-products triphenylphosphine oxide and water. The eluent was distilled to remove Et2O and to afford the product as a colorless liquid (1.0 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A mixture of ethyl 7-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indole-2-carboxylate (1.03 g), 8N aqueous sodium hydroxide solution (1.3 mL), tetrahydrofuran (5 mL) and ethanol (15 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.92 g, yield 90%) as colorless crystals. melting point>277° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])(O)=O.[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.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:27]3[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Reactant: OCc1cccc(B(O)O)c1
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: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(-c2cccc(CO)c2)cc2c(Br)ccnc21
Yield: 66 %

Procedure:
The above reaction was repeated two more times with 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15 g of a reported 90% pure lot from CiVenti, 29.1 mMol) and 3-(hydroxymethyl)benzeneboronic acid (4.0 g, 26.3 mMol the first time, then 3.7 g, 24.3 mMol the second time). In both reactions dioxane (300 mL), aq. sat. NaHCO3 (75 mL), and (1.0 g, 0.86 mMol) of Pd(PPh3)4 was used. The amount of a bis-coupled side product was reduced from 26% to 15% and 13% respectively (by LCMS) in each of the reactions. All three reaction products (derived from a total of 40 g of 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine, 90% pure lot from CiVenti=36 g, 77.7 mMol) were combined and purified by flash chromatography by silica gel (10 to 15% EtOAc/CH2Cl2) to give the title compound (22.77 g, 66%) as a white solid: MS (ES) m/e 443.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=5.1 Hz, 1H), 7.85-7.91 (m, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.63 (d, J=5.3 Hz, 1H), 7.59 (app. t, J=7.8 Hz, 2H), 7.53 (s, 1H), 7.44-7.50 (m, 3H), 6.75 (s, 1H), 5.35 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H).
Reaction SMILES: [OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:5]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: C[C@](O)(C(=O)O)c1ccccc1
Product: CN(C(=O)[C@](C)(O)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2R)-2-hydroxy-2-phenylpropanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a stirred mixture of methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.24 g, 0.94 mmol) and K2CO3 (0.156 g, 1.13 mmol) in 10 mL of DMF was added chloromethyl pivalate (0.17 g, 1.13 mmol) drop-wise at room temperature. Then the mixture was stirred at room temperature for 16 hours. The mixture was then poured into 30 mL of water, extracted with ethyl acetate (90 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4 to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.276 g, 79.5%) as a pale yellow solid. LCMS: (M+H)+=370; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.38 (s, 1H), 6.21 (s, 2H), 3.96 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:16][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[NH2:1])[C:8](=[O:9])[O:7][CH:6]2[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCC1OC(=O)c2cc(N)c([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(N)c(N)cc21

Procedure:
To a suspension of 3.75 g (15 mmol) of compound obtained in Example 22 in 150 ml of 95% ethanol there is added Raney nickel catalyst to hydrogenate at a hydrogen pressure of 1 kg/cm2. After the absorption of hydrogen has ceased, the catalyst is filtered off, and the filtrate is concentrated to dryness. The residue is crystallised from dilute ethanol, giving the title product.