Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O1CCOCC1>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=4)[CH:9]=3)[NH:4][N:3]=2)=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(N)c3c2)o1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(NC(=O)c4ccc(Cl)s4)c3c2)o1

Procedure:
300 mg of tert-butyl 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylate, 199 mg of 5-chlorothiophene-2-carbonyl chloride and 8 mg of 4-(dimethylamino)pyridine are stirred at 90° C. for 24 hours in 2 ml of pyridine and 100 μl of dioxane. The reaction mixture is evaporated, and the residue is purified by column chromatography. Yield: 260 mg (58%) of tert-butyl 5-{3-[(5-chlorothiophene-2-carbonyl)amino]-1H-indazol-5-yl}furan-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(NCC)C>CN(C=O)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.[Cu]I>[F:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][CH2:5]3)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: C#Cc1cccc(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C1NCc2cc(C#Cc3cccc(F)c3)ccc21
Temperature: 60 °C

Procedure:
To a solution of 5-bromoisoindolin-1-one III-3 (100 mg, 0.47 mmol) in DMF (2 mL) was added 3-fluorophenylacetylene III-4 (67 mg, 0.56 mmol), Pd(Ph3P)4 (27 mg, 0.02 mmol), CuI (9 mg, 0.04 mmol) and diethylamine (200 μL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc:hexanes (2:1, 8 mL) and washed with water (2×5 mL) and brine (5 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by mass directed preparative HPLC to afford 5-((3-fluorophenyl)ethynyl)isoindolin-1-one III-5 (42 mg, 35%) as a light brown solid; 1H-nmr (400 MHz, CDCl3) δ 7.92 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.40-7.31 (m, 2H), 7.28-7.22 (m, 1H), 7.14-7.07 (m, 1H), 5.36 (s, 2H); LC (214 nM) 3.38 min (>98%); MS (ESI) m/z=253.1.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[N+:15]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
First, 300 g of 9,10-dihydrophenanthrene were dissolved in 2 L of acetic acid, and then 450 mL of fuming nitric acid (d=1.50) were dropped to the mixture. The reaction solution was stirred at room temperature for 7 hours. The reaction solution was poured into 5 L of water, and then the precipitated crystal was separated by filtration and recovered. The resultant crystal was washed with water and methanol, and was then dried under reduced pressure. Thus, 280 g of an orange crystal were obtained (in 74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20]CC=C)[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.Cl[C:27]1[CH:32]=CC=C[C:28]=1Cl>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:32][CH:27]=[CH2:28])=[CH:17][C:16]([Cl:19])=[C:15]([OH:20])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1c(Cl)ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12
Product: C=CCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Temperature: 25 °C
Yield: 27 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-allyloxy-5-chlorobenzofuran (400 mg; 1.12 mmoles) in ortho-dichlorobenzene (15 mL) was refluxed under nitrogen for 1.5 hours. The reaction mixture was cooled to room temperature and purified by chromatography on silica gel using 20% ethylacetate as eluent to yield 110 mg (27%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-allylbenzofuran.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1cccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCN3CCCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCCC3)cc2)c1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(3-methoxyphenyl)-4-(4-(2-piperidinoethoxy)phenyl)chromane (0.355 g, 0.75 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[CH3:28][C@H:13]1[C@H:14]([N:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCNC[C@H]1C
Reaction time: 24 h

Procedure:
A mixture of trans-N-benzyloxycarbonyl-3-methyl-4-[(1-oxopropyl)phenylamino]-piperidine (1.5 g, 3.94 mmol), 10% Pd-C (200 mg), methanol (20 ml), and acetic acid (20 ml) is hydrogenated at 50 psi for 24 hours. The resultant suspension is filtered through a bed of Celite and the filtrate concentrated. The residue is diluted with ethyl acetate (50 ml), basified to pH 11 with 2N NaOH and shaken. The organic layer is separated, dried over magnesium sulfate, and concentrated to trans-3-methyl-4-[(1-oxopropyl)-phenylamino]-piperidine: 720 mg; 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 59.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), and 2-methylbenzoyl chloride (16 mg, 0.100 mmol), the title compound (13 mg, yield 59%) was obtained as off-white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccs4)c2)c1=O)CCCC3
Yield: 20 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 2-thiophenesulfonyl chloride (27 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 9 mg, yield 20%).
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]2[C:17]([CH3:29])=[C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[CH:20][C:4]=2[CH2:3]1.C(N1C(=O)[C@H](N[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:50][CH2:49]2)=[O:47])CC2C=C(C)C(NC(=O)OC(C)(C)C)=CC=2C1)C1C=CC=CC=1>>[CH2:10]([N:7]1[C:8](=[O:9])[C@H:2]([NH:1][C:46]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:50][CH2:49]2)=[O:47])[CH2:3][C:4]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[C:17]([CH3:29])[C:5]=2[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CN(Cc1ccccc1)C(=O)[C@H](NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1CN(Cc1ccccc1)C(=O)[C@H](N)C2
Product: Cc1c(NC(=O)OC(C)(C)C)ccc2c1CN(Cc1ccccc1)C(=O)[C@H](NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Yield: 94 %

Procedure:
(R)-tert-Butyl 4-amino-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate was reacted in a manner analogous to the preparation of (R)-tert-butyl 2-benzyl-7-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate. Title compound was obtained as off-white solid in 94% yield.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1[CH:40]=[CH:39][C:38]([C:41]2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=C[CH:42]=2)=[CH:37][CH:36]=1.C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH2:39][CH2:40][CH2:35][CH2:36][CH2:37][CH2:38][CH2:41][CH3:42])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 98 %

Procedure:
The compound of example 171 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-(n-octyl)benzoyl chloride.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]2[N:14]3[CH2:15][CH2:16][C@H:11]([C@H:12]([C:17]([OH:19])=[O:18])[CH2:13]3)[C@@H:10]2[OH:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH:51]([C:54]1[CH:55]=[CH:56][C:57]([O:62][CH3:63])=[C:58]([CH:61]=1)[CH2:59]Br)([CH3:53])[CH3:52]>COCCOC>[C:21]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:9]2[N:14]3[CH2:15][CH2:16][C@H:11]([C@H:12]([C:17]([O:19][CH2:59][C:58]4[CH:61]=[C:54]([CH:51]([CH3:53])[CH3:52])[CH:55]=[CH:56][C:57]=4[O:62][CH3:63])=[O:18])[CH2:13]3)[C@@H:10]2[OH:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C(C)C)cc1CBr
Reactant: O=C(O)[C@@H]1CN2CC[C@H]1[C@H](O)[C@@H]2C(c1ccccc1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: COCCOC
Product: COc1ccc(C(C)C)cc1COC(=O)[C@@H]1CN2CC[C@H]1[C@H](O)[C@@H]2C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a suspension of (3S,4R,5S,6S)-6-diphenylmethyl-5-hydroxy-1-azabicyclo[2.2.2]octane-3-carboxylic acid hydrochloride (obtained in Example 1 (iii); 110 mg, 0.3 mmol) in DME (3 ml) was added potassium t-butoxide (130 mg, 1.2 mmol) followed by 18-crown-6 (300 mg, 1.2 mmol) at room temperature. To this solution was added 5-isopropyl-2-methoxybenzyl bromide (300 mg, 1.2 mmol) in DME (3 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, quenched with H2O (10 ml), and extracted with CH2Cl2 three times. The combined extracts were dried over Na2SO4 and concentrated. The crude was purified by a column chromatography on silicagel to give a title compound (120 mg, 0.23 mmol, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCN(C)CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 1-methyl piperazine. LCMS (M+H)+=530.1/532.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([SH:9])[CH2:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([S:9][CH3:16])[CH2:4][N:3]=1
Reactant: CC1=CC(C)=NCN1S
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSN1CN=C(C)C=C1C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH were dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfate were added dropwise to this mixture at room temperature over the course of 10 minutes. After 1 hour, the aqueous phase was extracted 3 times with ether and dried over magnesium sulfate, and the solvent was distilled off. 15.9 g (97%) of crude product were isolated. 1H-NMR (270 MHz): 6.7 ppm (1H, s), 2.5 (3H, s), 2.3 (6H, s).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([C@@:16]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C@:16]([C:11]2[CH:10]=[C:9]([CH:14]=[C:13]([F:15])[CH:12]=2)[O:8][CH2:7][C:6]([OH:45])=[O:5])([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)COc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
To a solution of (S)-tert-butyl-2-(3-(1-(5-chloropyridin-2-yl)-1-(4-fluoro-3-(trifluoromethyl)benzamido)-2-phenylethyl)-5-fluorophenoxy)acetate (27 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added TFA (95 mg, 0.836 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed to give (S)-2-(3-(1-(5-chloropyridin-2-yl)-1-(4-fluoro-3-(trifluoromethyl)benzamido)-2-phenylethyl)-5-fluorophenoxy)acetic acid as an white foam (25 mg, 100% yield). LCMS: RT=4.08 min [M+H] 591.46 (LCMS Method 1); 1H NMR (400 MHz, CDCl3) δ 3.69 (d, J=12.74 Hz, 1 H), 4.40 (d, J=13.18 Hz, 1 H), 6.53 (d, J=7.47 Hz, 3 H), 6.76 (d, J=9.23 Hz, 1 H), 6.91 (s, 1 H), 7.05 (t, J=7.47 Hz, 2 H), 7.15 (t, J=7.47 Hz, 7.25 −7.34 (m, 2 H), 7.78 (dd, J=8.57, 2.42 Hz, 1 H), 7.86 (ddd, J=8.68, 2.31, 2.20 Hz, 1 H), 7.91-7.98 (m, 1 H), 8.36 (d, J=2.20 Hz, 1 H), 9.30 (s, 1 H).
Reaction SMILES: [Mg].II.[CH3:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][CH:10]=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](O)=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:4])[CH:10]=1)=[O:15]
Reactant: O=C(O)C(F)(F)C(F)F
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(C(=O)C(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring a solution of magnesium (14.1 g, 579 mmol) and iodine (one crumb) in diethyl ether (100 ml), 3-methylbromobenzene (90.0 g, 526 mmol) in diethyl ether (200 ml) was dropwise added at room temperature. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. The reaction solution was cooled to −78° C. and a solution of 2,2,3,3-tetrafluoropropionic acid (25.61 g, 175.4 mmol) in diethyl ether (100 ml) was dropwise added, and the mixture was heated under reflux for 4 hrs. To the reaction solution was dropwise added 1N hydrochloric acid under ice-cooling. The diethyl ether layer was separated, and the aqueous layer was extracted with diethyl ether. The recovered diethyl ether solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[S:8][C:7]([C:9](OC)=[O:10])=[C:6]([NH:13][CH3:14])[C:5]=1[CH3:15].Cl.[Cl-].[NH4+].C([N:21](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CO.O>[Br:3][C:4]1[S:8][C:7]([C:9]([NH2:21])=[O:10])=[C:6]([NH:13][CH3:14])[C:5]=1[CH3:15]
Reactant: CNc1c(C(=O)OC)sc(Br)c1C
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1c(C(N)=O)sc(Br)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Sodium hydroxide (4.27 g, 107 mmol) was dissolved with water (35 mL) and MeOH (140 mL). Then, methyl 5-bromo-4-methyl-3-(methylamino)thiophene-2-carboxylate (4.46 g, 16.7 mmol) was added to the mixture. The mixture was stirred at 70° C. overnight. After cooling in ice-water bath, 6 M HCl (11.9 mL, 71.4 mmol) was added, and the mixture was concentrated under reduced pressure. The residue was co-evaporated with toluene twice to give a yellow solid. This residue was mixed with ammonium chloride (38.1 g, 712 mmol), triethylamine (99 mL, 712 mmol) and DMF (300 mL), and the mixture was stirred for 5 min. Then, 1-hydroxybenzotriazole (32.7 g, 214 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40.9 g, 214 mmol) were added to the mixture, and stirring was continued for 3 days. The reaction mixture was poured into saturated aqueous NaHCO3 (1 L). Extraction with EtOAc (1 L), washing with saturated NaHCO3, drying over MgSO4, filtration and concentration under reduced pressure gave a brown oil. This oil was purified by column chromatography (Purif, silica gel, hexane to EtOAc) to afford the title compound (2.34 g, 56%) as a brown oil:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:21]=[CH:20][CH:19]=[N:18]4)=[CH:15][CH:14]=[CH:13][C:12]=3[F:22])=[O:10])[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[CH3:31][C:26]1[CH:27]=[C:28]([CH3:30])[N:29]=[C:24]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]([C:11]4[C:16]([N:17]5[N:18]=[CH:19][CH:20]=[N:21]5)=[CH:15][CH:14]=[CH:13][C:12]=4[F:22])=[O:10])[CH2:7]3)[CH2:2]2)[N:25]=1
Reactant: O=C(c1c(F)cccc1-n1nccn1)N1C[C@@H]2CCNC[C@@H]21
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4c(F)cccc4-n4nccn4)[C@H]3C2)n1
Yield: 51.7 %

Procedure:
(1R,6S)-3,8-Diazabicyclo[4.2.0]octan-8-yl(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Intermediate 29, 56 mg, 0.19 mmol), 2-chloro-4,6-dimethylpyrimidine (32 mg, 0.22 mmol) and DIPEA (96 μL, 0.56 mmol) in ACN (2 mL) were heated in a microwave reactor for 1 h at 150° C. Then the reaction mixture was diluted with water and extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated. Purification via prep HPLC (Agilent, basic) gave 40 mg (53%) of the title compound as a clear oil. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.0 [M+H]+. 1H NMR (CDCl3): 8.00-6.88 (m, 5H), 6.38-5.88 (m, 1H), 4.95-3.57 (m, 6H), 3.29-2.61 (m, 2H), 2.47-1.80 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23](O)=[O:24].[N:26]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23]([N:34]1[CH2:35][CH2:36][CH:31]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:32][CH2:33]1)=[O:24]
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Yield: 12 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a light yellow oil (12%). MS: 484.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc(N)nc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1oc(NC(C)=O)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 g (11.8 mmol) ethyl 2-amino-4-methyl-oxazole-5-carboxylate in 50 ml DCM are added 6.1 ml (35.3 mmol) DIPEA. To this mixture 0.92 ml (12.9 mmol) acetyl chloride are added and the reaction mixture is stirred at r.t. for 2 h. The mixture is diluted with further DCM and washed with water. The organic layer is separated, dried and the solvent is removed in vacuo.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:38]4[CH2:39][CH2:40][C@@H:36]([NH:35][CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CN[C@@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN[C@@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]