Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL), oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops) were added and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Next, to a suspension of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) in chloroform (60 mL), a solution of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride in chloroform (60 mL) was added dropwise under ice cooling and stirred at room temperature for 1 hour, followed by addition of water and chloroform under ice cooling to separate the organic layer. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to give 4-(benzyloxy)-5-bromo-N-methoxy-N-dimethylbenzamide. To a solution of this product in THF (150 mL), lithium aluminum hydride (1.96 g, 51.7 mmol) was added at −10° C. and stirred at the same temperature for 1 hour. The reaction mixture was diluted with 1N hydrochloric acid, followed by addition of ethyl acetate to separate the organic layer. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to give 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a solution of this product in toluene (120 mL), ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol) were added and heated under reflux for 1.5 hours using a Dean-Stark apparatus. Ethyl acetate was added to the reaction mixture to separate the organic layer. The organic layer was washed with water, saturated sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) and further purified by NH-type silica gel column chromatography (chloroform) to give the titled compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [CH3:1]N1CCCC1=O.[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][C:13]=1[NH2:19])[CH3:9].C[Sn](C)(C)C>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.O>[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:1])=[N:14][C:13]=1[NH2:19])[CH3:9]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1ccc(Cl)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)C
Solvent: O
Product: CCOC(=O)c1ccc(C)nc1N
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a N-methylpyrrolidinone (20 mL) solution of 2-amino-6-chloro-nicotinic acid ethyl ester (2.00 g, 7.78 mmol) described in Manufacturing Example 170-1-1 were added tetramethyltin (1.62 mL, 11.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (899 mg, 0.778 mmol), which was stirred under nitrogen atmosphere for 5 hours and 40 minutes at 130° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1), and then further purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (670 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29])[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COCOc1ccc(C=O)cc1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Temperature: 150 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1.4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:17]([O-])=O.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1.C(Cl)Cl>[NH2:17][C:3]1[C:2]([Cl:1])=[C:9]([N:10]2[CH2:15][CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:12][C:11]2=[O:16])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(N2CCNCC2=O)c(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This amine was dissolved in THF (2.000 mL) and DCM (2.000 mL), then TEA (0.030 mL, 0.214 mmol) was added followed by BOC2O (0.033 mL, 0.143 mmol). After stirring at room temperature for 2 h, LC-MS indicated completion, it was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate (20 mg) as an off-white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:10])C.[Na+].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([N:2]2[CH2:6][CH2:5][C@@H:4]([OH:10])[CH2:3]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1CCCC1
Reactant: O[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O[C@@H]1CCN(C2CCCC2)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
(R)-Pyrrolidin-2-ol hydrochloride (0.9 g; 7.31 mmol) was suspended in 50 ml of dichloromethane and sodium triacetoxyborohydride (4.37 g; 0.021 mol) was added. A solution of cyclopentanone (2.75 ml; 0.031 mol) in 530 ml of to dichloromethane was added drop-wise to the reaction mixture. The reaction mixture was maintained at room temperature overnight; it was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The water phase was concentrated in vacuo. The crude was treated with dichloromethane in order to separate the salts. The salts were precipitated and filtered. The organic phase concentrated in vacuo. 450 mg (2.90 mmol; 40% yield) of the desired compound were obtained.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[CH2:14]([NH:21][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)c1c(F)cc(F)c(F)c1NCc1ccccc1

Procedure:
A mixture of 19.4 g of 2,3,4,6-tetrafluorobenzoic acid, 200 ml of dioxane and 35.3 ml of benzylamine was heated under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and hydrochloric acid was added to adjust the pH of the solution to 3. The solution was then extracted with ethyl acetate. The extract was dried, treated with activated carbon and concentrated. Ether and n-hexane were added to the residue, and the crystals were collected by filtration to give 20.2 g of 2-benzylamino-3,4,6-trifluorobenzoic acid. m.p. 140°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[C:19]([C:23]1[O:24][C:25]([CH3:31])=[C:26]([CH2:28][CH2:29]O)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:29][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:24][C:25]=2[CH3:31])=[CH:8][C:7]=1[CH3:14]
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCO[C@@H](Cc1c(C)cc(OCCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the Mitsunobu-procedure described in example 1, step f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 51 e]) was reacted with 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (example 1, step e])) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (S)-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH:23][CH3:24])([CH3:22])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:23]([CH:20]([CH3:22])[CH3:21])[CH3:24])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (5.0 g, 16.3 mmol) and N-isopropyl-methylamine (5.95 g, 81.4 mmol) in DMSO (50 mL) at 75° C. according to the general procedure C. Obtained as a yellow solid (4.07 g, 73%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=C=N.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH:23]=[C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:16]=1>C(Cl)Cl>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH:23]=[C:24]2[CH2:25][CH2:26][N:27]([C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:28][CH2:29]2)[N:16]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1cccc(C#CC=C2CCN(C(=O)Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of phenylacetic acid (61.5 mg, 0.452 mmol) in 10 mL di CH2Cl2 was added PS-carbodiimide 1.25 mmol/g (480 mg, 0.6 mmol), while gently stirring at r.t. After 20 min., the Compound of Example 3 (64 mg, 0.301 mmol) was added. A very slow stirring was maintained overnight. Filtration, followed by washing the resin with CH2Cl2 and evaporation afforded a crude which was purified by flash chromatography (CHCl3-1.4 N MeOH/NH3 100:0.2) yielding the title product (80 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[S:18](Cl)([Cl:21])(=[O:20])=[O:19]>C1(C)C=CC=CC=1.ClCCl>[Cl:21][S:18]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:10])(=[O:20])=[O:19]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)Cl
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
A solution of L-proline methyl ester hydrochloride (0.33 g, 0.002 mole) in toluene (5 ml), dichloromethane (2 ml) and triethylamine (0.6 ml, 0.004 mole) was added dropwise over a period of 3 minutes to a cold (−20° C.) solution of sulfuryl chloride (0.32 ml, 0.0039 mole) in toluene. The mixture was stirred an additional 45 minutes at −20° C. The reaction was filtered and the solvent was removed under reduced pressure to give the title compound (0.40 g). 1H NMR (300 MHz, CDCl3) δ 2.13 (m, 2 H) 2.32 (m, 2 H) 3.58 (m, 1 H) 3.75 (m, 1 H) 3.79 (s, 3 H) 4.40 (dd, J=8.82, 4.04 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 3-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 79%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[C:10]([C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CCCCCC>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[C:10]([C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(F)c(Cl)c3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(F)c(Cl)c3)cccc12
Yield: 64.3 %

Procedure:
[1-Benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl 2-[1-benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl]-2-oxoacetate (0.139 g, 0.319 mmol), and potassium hydroxide (0.076 g, 1.35 mmol) in THF (2.5 mL) and water (2.5 mL) following the procedure described in Step 4 of Example 5. Following work-up, and trituration of the residue with hexane, a solid was obtained. Drying for 12 hours at 82° C. yielded the title compound as a yellow solid (0.0836 g, 64%), mp: 153-156° C. Mass spectrum (−ESI, [M−H]−) m/z 406; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.65 (s, 1H), 8.35 (m, 1H), 7.3-7.35 (m, 2H), 7.05-7.2 (m, 5H), 7.0 (s, 1H, J=7.1 Hz), 6.35 (d, 2H, J=6.9 Hz), 5.35 (d, 1H, J=16.6 Hz), and 5.15 ppm (d, 1H, J=16.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH2:4][Br:5].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[Br-:5].[F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH2:4][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Product: [Br-]
Temperature: 130 °C

Procedure:
The toluene solution from Stage 1 was mixed with triphenyl phosphine (1 g) and heated at 130° C. for 3 hours. After cooling, the solution was diluted with diethyl ether (5 cm3) and the title compound filtered off, washed with hexane (4×5 cm3) and dried by suction.
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:13].[K+].C1(C)C=CC=CC=1.[OH2:22]>C(O)CO>[C:1]1([C:7]2([C:11]([OH:22])=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: N#CC1(c2ccccc2)CCC1
Reactant: O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: OCCO
Product: O=C(O)C1(c2ccccc2)CCC1
Temperature: 160 °C

Procedure:
Intermediate 60 (2.6 g, 16.54 mmol) was dissolved in ethyleneglycol and added potassium hydroxide (5.6 g, 99.2 mmol). This mixture was heated to 160° C. for 2 h. After two hours reaction mixture was cooled to rt and toluene and water were added. Aqueous layer separated and acidified with HCl and pH adjusted to 4. Aqueous layer extracted with ethyl acetate and ethyl acetate layer was dried on anhydrous sodium sulphate. Ethyl acetate removed on rotavapour to obtain the title compound (930 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:15](C(OC(C)(C)C)=O)[N:14]=[C:13]([CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:12]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH2:24][CH2:23][C:13]2[CH:12]=[C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:15][N:14]=2)[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccccc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Benzoyl chloride (56 μl, 0.47 mmol, 1.1 eq) was added dropwise to a mixture of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (150 mg, 0.43 mmol, 1 eq) and pyridine (104 μl, 1.29 mmol, 3 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 2 h, a solution of TFA (321 μl, 4.32 mmol, 10 eq) in DCM (2.7 ml) was added dropwise and stirring was continued for a further 1 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless foamy solid (100 mg, 66% yield).
Reaction SMILES: [CH2:1]([C:3]([CH2:8]O)([CH2:6][OH:7])[CH2:4][CH3:5])O.[C:10]1(O)[C:11](=[CH:13][C:14](=[CH:16][CH:17]=1)O)[CH3:12].[OH-:19].[K+]>>[CH3:13][CH:14]([C:14]1[CH2:16][CH2:17][C@H:10]2[C:11](=[CH:12][CH2:5][C@H:4]3[C@@:3]([C:6]([OH:19])=[O:7])([CH3:8])[CH2:1][CH2:12][CH2:11][C@@:10]32[CH3:17])[CH:13]=1)[CH3:16]
Reactant: Cc1cc(O)ccc1O
Reactant: [OH-]
Reactant: CCC(CO)(CO)CO
Agent: [K+]
Product: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
5 10.26 kg of Portuguese balsam resin WW 4.02 kg of trimethylolpropane and 0.007 kg of toluhydroquinone were weighed into a 15 liter stirred tank equipped with a distillation attachment and nitrogen (30 to 40 l/h) was passed over the mixture for 30 minutes. The stream of nitrogen was reduced to 8 to 10 l/h and the mixture was heated to 120 to 130° C. When the resin had melted, the stirrer Incas switched on. The reaction mixture was subsequently heated to 140° C. over a period of 2 h, and then maintain the following temperatures: 1 h at 140° C., 1 h at 150° C. 1 h at 160° C., 1 h at 170° C., 1 h at 180° C., 1 h at 200° C. and I h at 220° C. The stream of nitrogen was then increased to 20 l/h and the reaction mixture was heated to 230° C. and stirred at this temperature until the acid number was less than 10 mg KOH per g substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.CCOCC>[Br-:1].[Br:1][CH2:2][CH2:3][CH2:4][P+:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCBr
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1,3-Dibromopropane (28.8 ml) was added to a solution of triphenylphosphine (15.0 g) in toluene (30 ml). The mixture was stirred at 70° C. under nitrogen for 16 hours, then cooled, diluted with ether (150 ml) and filtered to give 3-bromopropyltriphenylphosphonium bromide.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:31][N+:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[S:34][C:33]=1SC>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[C:33]2[N:32]([CH3:31])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[S:34]2)[S:7][C:6]1=[N:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4]
Reactant: CSc1sc2ccccc2[n+]1C
Reactant: CCCCN1C(=O)CSC1=Nc1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(=C2Sc3ccccc3N2C)SC1=Nc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
To a 8 mL vial was added 3-(3-butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile (55 mg, 0.20 mmol), 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate (73 mg, 0.20 mmol), anhydrous MeCN (2 mL) and TEA (70 μL, 0.50 mmol). The reaction mixture was first warmed to 50° C. and the resulting solution was allowed to stir at room temperature for 16 h. The product mixture was concentrated under reduced pressure, chromatographed (silica gel, 1:99 MeOH/DCM) and then recrystallized from MeCN to give the title product (11.8 mg) as a yellow solid.