Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>C(Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:12](=[O:15])[CH2:13][CH3:14])[CH:7]=1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: CCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 2.01 g of 1-chloro-2,4-dimethoxybenzene and 1.08 g of propionyl chloride in 20 ml of CCl4 is cooled to 0° C., and a solution of 1.3 ml of TiCl4 in 7 ml of CCl4 is added dropwise. The reaction mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. It is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (80:20; v/v) mixture. 1.14 g of expected product, m.p.=115° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[C:32]([N:20]2[CH2:19][CH2:18][N:17]([C:9]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:13][N:12]=[C:11]4[NH:14][CH:15]=[CH:16][C:10]=34)[CH2:22][CH2:21]2)=[O:33])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
5-(3-Fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.062 g, 0.168 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0604 g, 0.201 mmol) were placed in DCM (3 mL) at room temperature. HOBT-H2O (0.0360 g, 0.235 mmol), EDCI (0.0418 g, 0.218 mmol), and DIEA (d 0.742; 0.146 mL, 0.840 mmol) were then added. The reaction was stirred at room temperature for 2 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil. The oil was purified by column chromatography (500:5 D CM: MeOH) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.045 g, 46.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl.N([O-])=O.[Na+].[C:18]([O-])(=[O:20])C.[Na+].C=NO.Cl.C=NO.S([O-])([O-])=O.[Na+].[Na+].NC1C=CC=CC=1>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([CH:18]=[O:20])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: C=NO
Agent: Cl
Agent: O=N[O-]
Solvent: Nc1ccccc1
Solvent: O
Product: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Yield: 8.8 %

Procedure:
To a suspension of 4-chloro-3-trifluoromethylaniline (ex Fluorochem) (15.9 g) in water (16 ml) was added concentrated hydrochloric acid (18 ml) Ice (30 g) was added and the mixture cooled to 0° and treated with sodium nitrite (5.6 g) in water (8 ml). After 15 minutes the mixture was made neutral to congo red with sodium acetate (8 g) in water (10 ml). A solution of formaldoxime, prepared from formaldoxime hydrochloride (ex Lancaster) (9.9 g) and sodium acetate (12 g) (ex BDH) in water (57 ml), at 10° was treated with cupric sulphate (2 g) (ex BDH) and sodium sulphite (0.34 g) followed by sodium acetate (55 g) in water (60 ml). The previously prepared mixture (from the aniline) was added dropwise at 10°-15°. After one hour at 15° hydrochloric acid (77 ml) was added and the mixture worked up in the usual manner. Purification by distillation (80°, 0.5 mmHg) gave 4-chloro-3-trifluoromethylbenzaldehyde (1.5 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:32])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[N:10]([CH2:24][C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:9]2=[O:31].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:28]([NH:27][C:25]([CH2:24][N:10]1[C:9](=[O:31])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:4][C@@H:3]([CH3:32])[CH2:2][O:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=2)[N:12]=[C:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[O:26])([CH3:29])[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)CO)cc3c(=O)n2CC(=O)NC(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: -78 °C

Procedure:
To a suspension of (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (0.96 g, 2.18 mmol) in dichloromethane (100 mL) cooled to −78° C. under argon was added methanesulfonyl chloride (2.50 g, 1.7 mL, 21.90 mmol) dropwise over 5 min, followed by dropwise addition (10 min) of triethylamine (2.21 g, 3.10 mL, 21.9 mmol). The reaction mixture was warmed to −30° C. over 60 min followed by warming to room temperature over 15 min after which time the reaction was found to be complete (HPLC monitoring). The reaction mixture was diluted with ethyl acetate (300 mL), poured into ice water (100 mL) and the organic phase washed with 1N HCl (aq.) (2×200 mL), sat. NaHCO3 (aq.) (1×200 mL) and brine (1×200 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester as a pale yellow solid (1.13 g, 2.18 mmol, 100%, 91% purity by LC-MS).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:12](=[O:13])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cnc2[nH]ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cnc2[nH]ccc2c1)OCc1ccccc1
Temperature: 0 °C
Yield: 76.8 %

Procedure:
1H-pyrrolo[2,3-b]pyridin-5-amine (9.45 g, 71.05 mmol) was dissolved in THF (150 mL) and stirred at 0° C. under an atmosphere of nitrogen. Benzyl chloroformate (20.3 mL, 142.10 mmol, 2.0 Eq) was added dropwise over a period of 15 minutes and the mixture allowed to stir at room temperature for 30 minutes. The mixture was treated with 4M NaOH (aq) (53.3 mL, 213.16 mmol, 3.0 Eq) over a period of 15 minutes and the resultant brown solution left to stir for 16 hours. The reaction mixture was taken to pH 4 (125 mL of 10% aq. citric acid) and the 2 layers were separated. The aqueous layer was back extracted with EtOAc and the combined organics were dried over magnesium sulphate, filtered and dried under vacuum. The crude product was purified by column chromatography (50% EtOAc/Petroleum Ether) to give 14.59 g (77%) of pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: O=Cc1cc(Cl)ccn1
Agent: Cl
Product: O=C(NC1CCCCC1)C1CCN(Cc2cc(Cl)ccn2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 4-chloro-pyridine-2-carboxaldehyde and piperidine-4-carboxylic acid cyclohexylamide hydrochloride as in 3.01c: LC-MS A: tR=0.58 min; [M+H]+=380.19.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[CH2:9]([NH:16][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: NCc1ccccc1
Solvent: O
Product: Oc1cccc(NCc2ccccc2)c1

Procedure:
According to this invention, water-soluble coumarins and azacoumarins having the structures: ##STR2## wherein R is CH3 or CF3 and wherein R1 is H or CH3 are prepared. The coumarins are prepared by means of a three step process involving (1) heating resorcinol and benzylamine to form 3-benzylaminophenol, (2) reacting the 3-benzylaminophenol with ethyl acetoacetate or ethyl trifluoroacetoacetate in the presence of anhydrous zinc chloride and absolute ethanol to form 7-benzylamino-4-methylcoumarin or 7-benzylamino-4-trifluoromethylcoumarin, (3) sulfonating the product of step (2) with oleum and (4) neutralizing the sulfonate formed in step (3) with sodium bicarbonate. The azacoumarins are prepared by a similar process except that 6-chloro-2-pyridinol and either benzylamine or benzylmethylamine are used as the starting compounds (the step (1) reactants).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[C:4]([O:14]C)[CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:9])=[O:10])[CH:7]=1
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OC)c1
Agent: BrB(Br)Br
Product: CCCS(=O)(=O)c1cc(O)cc(Br)c1
Yield: 77.9 %

Procedure:
A similar procedure as described in Example 47, step 4 was used, starting from 1-bromo-3-methoxy-5-(propane-1-sulfonyl)-benzene (1.55 g, 5.29 mmol) and boron tribromide (10.57 mL, 10.57 mmol, 1.0M in dichloromethane) to afford 3-bromo-5-(propane-1-sulfonyl)-phenol (1.15 g, 78%) as a white solid: ES(+)-HRMS m/e calcd for C9H11BrO3S (M+Na)+ 300.9504, found 300.9503.
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C>[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH:67][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH2:62][CH2:61]1
Reactant: CN1CCC(CN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC1CCN(C)CC1

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (300 mg, 0.48 mmol), DIPEA (136 mg, 2.2 eq.) and C-(1-methyl-piperidin-4-yl)-methylamine TFA salt (186 mg, 1.1 eq.) in DMF (5 mL) was stirred at rt for 72 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [OH2:1].O.O.O.O.O.[Cl-:7].[Cr+3:8].[Cl-].[Cl-].[Cl-].[OH:12]CC[N+](C)(C)C.O.O.[F-].C([N+](CC)(CC)CC)C.O.O.O.O.O.[OH-].C[N+](C)(C)C>[Cl-].OCC[N+](C)(C)C.[Ni]>[OH2:12].[OH2:1].[OH2:12].[OH2:12].[OH2:12].[OH2:12].[Cl-:7].[Cr+3:8].[Cl-:7].[Cl-:7].[Cr:8]
Reactant: C[N+](C)(C)CCO
Agent: [Cr+3]
Agent: [Ni]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Product: [Cr]
Temperature: 80 °C

Procedure:
We have found that the presence of specific additives, not generally recognised as brighteners, in 2:1 chromium (III) chloride hexahydrate-choline chloride can significantly brighten the electrodeposit. For example when 10% of choline chloride is replaced by tetraethylammonium fluoride dihydrate or tetramethylammonium hydroxide pentahydrate thin semi-bright pale blue chromium deposits can be obtained. Approximately 6 ml of 2:1 chromium (III) chloride hexahydrate-[choline chloride (90%) tetraethylammonium fluoride dihydrate (10%)] was prepared by combining the reactants in a beaker and heating at 80° C. The green liquid was poured into an electrochemical cell (internal diameter of 23 mm) held in an oil bath at 60° C. Mild steel (50 mm by 10 mm and 1 mm thick), cleaned in the usual way, was fixed to the inside edge of the cell opposite a nickel counter electrode. The mild steel plate and counter-electrode were then connected to the negative and positive terminals respectively of a Thurlby Thander power pack. Using current densities between 8 and 16 mAcm−2 and deposition times between 10 and 30 minutes semi-bright chromium deposits were obtained. The procedure was repeated using approximately 6 ml of 2:1 chromium (III) chloride hexahydrate-[choline chloride (90%) tetramethylammonium hydroxide pentahydrate (10%)]. With a current density of 2 mAcm−2 thin pale blue semi-bright homogenous chromium deposits were obtained after 30 minutes.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:21])[C:17](Br)([F:19])[F:18])[CH3:14]>CS(C)=O.[Cu]>[CH2:13]([O:15][C:16](=[O:21])[C:17]([C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1)([F:19])[F:18])[CH3:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
To a solution of 4-iodo-2-methyl-6-nitroaniline (2.78 g, 10 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (2.03 g, 10 mmol) in anhydrous DMSO (20 mL) was added copper powder (1.28 g, 20 mmol). The mixture was purged with N2 and heated at 60° C. in a sealed vial for 14 h. After being cooled to the room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (300 mL). The resulting mixture was basified to pH=8.5 with saturated aqueous Na2CO3 solution and was extracted with EtOAc (3×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (40:1 hexanes/EtOAc) to afford the title compound (1.79 g, 65%). 1H NMR (CDCl3) δ 1.36 (t, 3H), 2.30 (s, 3H), 4.36 (q, 2H), 6.41 (br s, 2H NH), 7.51 (s, 1H), 8.33 (s, 1H). ESI-MS m/z 275 (MH+), 255 (M-F)+, 297 (M+Na)+, 549 (2M+1)+ and 571 (2M+Na)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:27])=[O:28])=[CH:21][CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: NS(=O)(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 37 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.075 g, 0.28 mmol) was reacted with (4-aminophenyl)methanesulfonamide (0.058 g, 0.31 mmol) to afford the title compound (0.043 g, 58%) as a white solid. MW=414.91. 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.32-8.21 (m, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.57-7.50 (m, 2H), 7.36 (d, J=8.6 Hz, 2H), 6.85 (s, 2H), 4.25 (s, 2H), 2.99-2.86 (m, 4H), 2.18-2.05 (m, 2H); APCI MS m/z 415 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21]1([CH:27]([NH2:31])[CH:28]([OH:30])[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CC#N>[OH:30][C@H:28]([C@H:27]([NH:31][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:29]
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl
Reactant: CC(O)C(N)c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@H](c1ccccc1)[C@H](C)O

Procedure:
Prepared as described in Ex. 1, starting from 11.08 g (39.33 mmol) of crude 3-methyl-2-phenylquinoline-4-carbonylchloride, 4.87 g (32.20 mmol) of 1-phenyl-2-hydroxypropylamine and 10.33 ml (74.14 mmol) of TEA in 150 ml of a 1:1 mixture of dry CH2Cl2 and CH3CN.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.O.[CH2:12](O)[CH3:13]>C(C=O)=O>[Cl:1][C:2]1[C:7]2[C:6](=[N:9][CH:12]=[CH:13][N:8]=2)[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(Cl)c1N
Agent: O=CC=O
Solvent: O
Product: Clc1cc2nccnc2c(Cl)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of the solution of 2,6-dichloropyridine-3,4-diamine (7.85 g, 0.044 mol) in ethanol and 40% glyoxal solution in water (26 g, 0.178 mol) was refluxed overnight. It was then cooled to ambient temperature, and the precipitates were collected, washed with EtOH, and dried in vacuo to give the title compound (7.32 g, 83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[C:5]2[CH3:20].[C-:21]#[N:22].[Na+].C(OCC)(=O)C.O>CN1C(=O)CCC1.[Cl-].[Na+].O.[Ni](Br)Br>[C:21]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[C:5]2[CH3:20])#[N:22]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)ccc32)cc1
Agent: Br[Ni]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3cc(C#N)ccc32)cc1
Temperature: 180 °C
Yield: 99.4 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)-3-methylindazole 105 (0.12 g, 0.363 mmol) in NMP (N-methylpyrrolidinone; 2 mL) was added sodium cyanide (0.035 g, 0.714 mmol) and nickel bromide (0.079 g, 0.362 mmol). The reaction mixture was heated in a microwave reactor at 180° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washer with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-cyano-N-(4-methoxybenzyl)-3-methylindazole 106 (0.1 g, 0.361 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 43.9 %

Procedure:
To a solution of 5-methoxy-2-phenylindole (245 mg) in N,N-dimethylformamide (4.5 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 72 mg) under cooling with ice, and the mixture was stirred at room temperature for 75 minutes. Then a solution of 3-(benzyloxy)benzyl bromide (365 mg) in N,N-dimethylformamide (1 mL) was added dropwise, and the mixture was stirred at 80° C. for 15 hours. The reaction mixture was cooled to room temperature. A saturated aqueous ammonium chloride solution-water (2/1) were added and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography to obtain the title compound (202 mg).
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Fe]>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Product: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield by reducing trans-N-decyl-2-(4-nitrophenyl)cyclopropanecarboxamide with iron powder in glacialacetic acid, in a manner analogous to Preparation 34.
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:8].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH2:44])[NH:42][N:43]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH:44][C:7]([C:9]3[S:13][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[CH:11][CH:10]=3)=[O:8])[NH:42][N:43]=2)[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at 20° C. for 20 h. The temperature was increased to 60° C. and the reaction mixture was stirred for 20 h and then allowed to cool. The reaction mixture was diluted with acetone (10 ml) and quenched with damp solid sodium sulphite. The mixture was stirred for 30 mins, and then a solution of 10% methanol in DCM (10 mL) was added and the mixture stirred for a further 30 mins. The suspension was filtered and the solid washed with 10% methanol in DCM (20 mL); the combined filtrates were evaporated to give a yellow foam. The crude product was purified by silica column chromatography, eluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated to dryness to afford the crude product. This was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate (0.272 g, 50.2%) as a white dry film. 1H NMR (500.13 MHz, DMSO-d6) δ 1.46 (9H, s), 2.89-2.90 (6H, m), 3.22 (4H, t), 3.52 (4H, t), 3.75 (6H, s), 6.18 (1H, d), 6.27 (1H, s), 6.34 (1H, t), 6.42-6.42 (2H, m), 7.72 (1H, d), 9.81 (1H, s), 11.71 (1H, s); MS: m/z 542 (MH+)