Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.ClCl.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]=[CH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccc(Br)cc1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)C=CCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2 Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>FC(F)(F)C(O)=O>[NH2:9][C:10]1[C:19]([I:1])=[CH:18][C:17]([Br:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)cc(I)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1-Iodo-pyrrolidine-2,5-dione (10.35 g, 46.0 mmol) was added in one portion to a solution of methyl 2-amino-5-bromo-benzoate (10.35 g, 45.0 mmol) in trifluoroacetic acid (90 mL) at ambient temperature. The reaction was stirred for about 1 hour at ambient temperature then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (150 mL), washed with saturated Na2CO3 solution (2×150 mL) and a 10% aqueous solution of Na2S2O4 (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated to yield methyl 2-amino-5-bromo-3-iodo-benzoate (15.5 g, 97%) as a yellow solid; RP HPLC (Table 1, Method e) Rt=2.45, 1H NMR (DMSO-d6, 400 MHz) δ 3.83 (s, 3H), 7.74 (broad s), 2H), 7.86-7.88 (d, 2H), 8.00-8.02 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:25]([O-:27])=[O:26])[C:5]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:24]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][CH:10]([C:8]1[N:7]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:24]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:3]=[C:4]([N+:25]([O-:27])=[O:26])[C:5]=2[N:9]=1)[CH3:12]
Reactant: C1COCCN1
Reactant: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 6-bromo-2-(1-methylethyl)-1-(1-naphthalenylmethyl)-4-nitro-1H-benzimidazole (2.05 g), morpholine (1.26 g), Pd2(dba)3 (0.46 g), Cs2CO3 (2.36 g) and X-Phos (0.41 g) in dioxane (30 mL) was degassed with nitrogen and then stirred at 80° C. overnight. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was then purified by silica gel chromatography eluted with (EtOAc:petroleum ether=1:1) to afford the desired product as a yellow solid (1.6 g, 77%). LC-MS: m/e=431 [M+1]+
Reaction SMILES: C([OH:3])C.[OH-].[Na+].[CH3:6][C:7]1[C:8]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:9]=2[C:10]2[C:11](=[O:24])N(C3C=CC(C)=CC=3)[C:13](=[O:16])[C:14]=2[CH:15]=1.Cl>O.C(OCC)(=O)C>[CH3:6][C:7]1[CH:15]=[C:14]2[C:13](=[O:3])[O:16][C:11](=[O:24])[C:10]2=[C:9]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:8]=12
Reactant: Cc1ccc(N2C(=O)c3cc(C)c4oc5ccccc5c4c3C2=O)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(c3c1oc1ccccc13)C(=O)OC2=O
Temperature: 25 °C
Yield: 91 %

Procedure:
5 ml of ethanol and 1.2 ml of a 5 N aqueous sodium hydroxide solution were added to 200 mg of 5-methyl-2-(4-methylphenyl)-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione. The mixture was refluxed for 30 minutes. Thereto was added 1.2 ml of concentrated hydrochloric acid. The resulting mixture was refluxed for 1 hour and then cooled to room temperature. Then, thereto were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 2.0 ml of acetic anhydride. The mixture was refluxed for 30 minutes, and then concentrated to dryness under reduced pressure. The residue was washed with diethyl ether and dried to obtain 140 mg (yield: 91%) of 4-methyldibenzofuran-1,2-dicarboxylic anhydride as light yellow crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:27][C:22]2=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:25][C:23]3=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=[C:22]3[CH:27]=2)(=[O:29])=[O:30])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)nc2s1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)nc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 6-chlorothieno[2,3-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2 Cl2 to 25% EtOAc/CH2Cl2 to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>ClCCl.CN(C=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:30]([NH:29][C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)=[S:31])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A solution of 3-amino-N-(3-chloro-4-methylphenyl)-4-methoxy-benzamide from Example 12 (0.581 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol) in dichloromethane (40 mL) and DMF (3 mL) was allowed to stand at room temperature. After 16 hours, filtration afforded the product (0.57 g); m.p. 195-196° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][C:14](=[O:32])[CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH2:29]O)[CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[CH3:12].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:32])[CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH2:29][O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=2)[CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=1)[CH3:12]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CO)C(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(C(COc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenol (818 mg, 4.07 mmol) and 3-[4-(1-hydroxymethyl-2-methyl-propyl)-benzoylamino]-propionic acid ethyl ester (1.0 g, 3.26 mmol) in anhydrous toluene (15 mL) is degassed and filled with nitrogen 3 times. Tributylphosphine (1.21 mL, 4.89 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.23 g, 4.89 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is loaded on a silica gel column and purified using hexanes/ethyl acetate. MS (ES): 488.2 [M+H]−.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.Cl.[OH-].[NH4+]>N1C=CC=CC=1>[CH3:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[S:10][C:11]=1[CH3:15]
Reactant: COc1ccc(-c2nc(C)c(C)s2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(O)cc2)sc1C
Temperature: 0 °C
Yield: 58.6 %

Procedure:
The product of part (a) (70.7 g) was added to 470 g pyridine saturated with hydrogen chloride gas, and the mixture was heated 2 hours at reflux. The reaction mixture was poured into 3000 ml ice-water, made basic with ammonium hydroxide, and the solid product was collected. The latter was purified by recrystallization from toluene to give 38.8 g 4-(4,5-dimethyl-2-thiazolyl)phenol, m.p. 194-195° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][CH:20]=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccoc1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2occc2c1
Yield: 60.4 %

Procedure:
Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(furan-3-yl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 5.2 g (29 mmol, 61%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:31][C:30]4([CH2:35][CH2:34][NH:33][CH2:32]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[CH2:40]=O.[BH4-].[Na+]>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:31][C:30]4([CH2:35][CH2:34][N:33]([CH3:40])[CH2:32]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: C=O
Reactant: O=C(Nc1cn(CC(=O)N2CC3(CCNC3)C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: CN1CCC2(C1)CN(C(=O)Cn1cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n1)C2
Temperature: 90 °C

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diaza-spiro[3.4]oct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (70 mg, 0.13 mmol) and paraformaldehyde (19 mg, 0.63 mmol) were stirred in 2,2,2-trifluoroethanol for 15 minutes. Sodium borohydride (14 mg, 0.38 mmol) was added and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was quenched with MeOH. The mixture was loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a crude product which was purified by HPLC (Method 1). The pure fractions were loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave the free base which was crystallised from MeOH/Et2O. The title compound was obtained as a white solid (28 mg, 39%). LCMS (Method 5) [M+H]+=570.9, RT=2.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.0 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 8.15 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.9 Hz), 7.57 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 2H, J=4.3, 7.1 Hz), 7.25 (t, 1H, J=73.5 Hz), 4.94 (s, 2H), 4.04 (q, 2H, J=8.8 Hz), 3.90-3.81 (m, 2H), 2.69 (s, 2H), 2.27 (s, 3H), 2.03 (dd, 2H, J=6.8, 6.8 Hz).
Reaction SMILES: Cl.C([Si](C)(C)[O:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][C:21]=3[Cl:33])[C:15]2=[O:34])[CH2:10][CH2:9]1)(C)(C)C>CO>[ClH:26].[Cl:33][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][CH:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([OH:7])[CH2:9][CH2:10]2)[C:15]1=[O:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(-c4cccnc4)cc3Cl)C2=O)CC1
Agent: Cl
Solvent: CO
Product: O=C1C(Cc2c(Cl)cc(-c3cccnc3)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: 40 °C

Procedure:
Add HCl (0.015 mL) to 1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-pyridin-3-yl-benzyl)-pyrrolidin-2-one (Preparation 75) (0.027 G, 0.0506 mmol) in methanol (2 mL) and heat to 40° C. for 1 hour. Concentrate under reduced pressure to give the title compound (0.017 g): mass spectrum (m/z):420(M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:5]=2[C:4](=[O:13])[NH:3]1.C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=[O:22])C=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:21]([O:23][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[NH:3][C:4](=[O:13])[C:5]=2[N:11]=1)(=[O:22])[CH3:16]
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Yield: 66 %

Procedure:
1.77 g of 1 (10 mmol) in 50 ml of glacial acetic acid containing 6.5 g of MCPBA (57-85%) was refluxed for 3 hours. Acetic anhydride (40 ml) was added to the hot reaction mixture and the refluxing was continued for another half an hour. The clear brown solution was evaporated to dryness and the solid was stirred with ether (100 ml) and filtered. The solid was crystallized from ethanol to give 1.55 g (66%) of 2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 82.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 3, 4 g, 7.1 mmol) in tetrahydrofuran (5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 15 mL, 15 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.5 g, 83.3%) as a white solid: LC/MS m/e calcd for C23H24N2O4S [M+H]+ 425.52, observed 424.9.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([NH:6]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.[ClH:16]>>[ClH:16].[F:1][C:2]([F:15])([F:14])[C:3]1([NH2:6])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(C(F)(F)F)CC1
Agent: Cl
Product: NC1(C(F)(F)F)CC1
Yield: 91 %

Procedure:
Tert-butyl 1-(trifluoromethyl)cyclopropylcarbamate (4.08 g, 18.3 mmol) was suspended in 1 N HCl(aq) (150 mL) and stirred at reflux for 3.5 h. The solution was concentrated in vacuo and the residue was triturated with acetone. The filtrate was collected, concentrated, and the residue triturated with diethyl ether to afford 2.67 g (91%) of 1-(trifluoromethyl)cyclopropylamine hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][CH:4]([P:8]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)(=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Reaction time: 12 h

Procedure:
A solution of 38 bg of ethyl diethoxymethyl(benzyl)phosphinate in 300 ml of absolute ethanol is treated with 20 g of Raney nickel and the suspension is hydrogenated at 110° C. and 150 bar for 12 hours. After this time the mixture is filtered through celite® and the filtrate is evaporated to dryness. Distillation of the residue in high vacuum gives ethyl diethoxymethyl(cyclohexylmethyl)phosphinate of b.p. 120° (10-2 mbar). 1H-NMR (CDCl3): δ (ppm)=, 4.62 (1H, d, CHP), 4.17 (2H, m, CH2OP), 3.84+3.69 (2H, m, 2×CH2OC), 1.88 (3H, m, CH2P+CH), 1.68 (6H, m, 3×CH2), 1.30 (13H, m, 3×CH3 +2×CH2).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-benzoic acid (40.3 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 46 mg (38.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.47%, 1H NMR: (DMSO) δ 8.7-8.6 (bs, 1H), 8.02-7.92 (d, 2H), 7.84-7.7 (q, 4H), 7.6-7.38 (m, 7H), 4.24 (d, 1H), 4.18 (d, 1H), 3.8-3.6 (m, 4H), 3.56-3.46 (m, 2H), 3.26-3.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:25]3[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:2].C[N:30](C)[CH:31]=[CH:32][CH:33]=O.C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:25]3[C:24]4[N:30]=[CH:31][CH:32]=[CH:33][C:23]=4[CH2:22][CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CN(C)C=CC=O
Reactant: CCN(CC)CCCOc1ccc(NC(=O)c2n[nH]c3c2C(=O)CCC3)cn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)CCCOc1ccc(NC(=O)c2n[nH]c3c2-c2ncccc2CC3)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [6-(3-diethylamino-propoxy)-pyridin-3-yl]-amide (192 mg, 0.50 mmol), 3-(dimethylamino)-acrolein 0.15 mL (1.50 mmol), ammonium acetate (384 mg, 5.00 mmol), and acetic acid (2.0 mL) is stirred under nitrogen at 100° C. for 16 h, poured into ice-cold 10% NaCl (20 mL), treated with 10 N NaOH to pH 12 and extracted with chloroform (30 mL). The extract is concentrated under reduced pressure and the residue is chromatographed on silica gel using chloroform-methanol-30% ammonium hydroxide (90:9:1, v/v/v) as an eluent to give pure 5,7-dihydro-6H-pyrazolo[3,4-h]quinoline-9-carboxylic acid [6-(3-diethylamino-propoxy)-pyridin-3-yl]-amide. 1H NMR (CDCl3) t, J=7.1 Hz, 6H), 1.96 (m, 2H), 2.57 (q, J=7.1 Hz, 4H), 2.65 (m, 2H), 3.10 (m, 4H), 4.33 (t, J=6.3 Hz, 2H), 6.80 (d, J=8.8 Hz, 1H), 7.21 (dd, J=7.7 and 4.9 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 8.32 (dd, J=8.9 and 2.7 Hz, 1H), 8.44 (d, J=2.7 Hz, 1H), 8.47 (dd, J=4.9 and 1.1 Hz, 1H). MW 420.519; MS (M−H)− 419.