Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC1OCCC1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Solvent: CC1CCCO1
Solvent: O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (15.2 g, 41.16 mmoles) is charged into a 250 mL 3-necked round bottomed flask, followed by addition of 2-MeTHF (61 mL, 4.0 volumes), the yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (19 g, 218.18 mmoles) is added over 2-5 minutes. Contents are heated to reflux and maintained at reflux for 12 hr. The slurry is cooled to 25° C., followed by addition of 2-MeTHF (53 mL, 3.5 volumes) and water (38 mL 2.5 volumes). The reaction mixture is warmed to 40° C., where upon a homogenous solution with two distinct layers formed. The layers are separated, the organic layer is filtered and concentrated to ˜3 volumes at atmospheric pressure. Four volumes 2-propanol (61 mL) are added. The solution is concentrated to ˜3 volumes followed by addition of 4 volumes 2-propanol (61 mL), re-concentrated to ˜3 volumes, followed by addition of another 6 volumes 2-propanol (91 mL), and refluxed for 15 min. The clear solution is gradually cooled to 75° C., seeded with 0.45 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 2 mL 2-propanol, rinsed with an additional 2 mL 2-propanol and transferred to a crystallization flask. The slurry is cooled to between 0-5° C., maintained for 1 hr, filtered and the product rinsed with 2-propanol (30 mL, 2 volumes). The solid is dried at 60° C. in a vacuum oven to afford 16.92 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine. Purity of product by HPLC assay is 100.00%. XRPD and DSC data of product is consistant with reference sample. MS (ES)=420 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C(Cl)Cl>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Clc1ncccn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3ncccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (300 mg, 0.62 mmol) and 2-chloropyrimidine (71 mg, 0.68) were stirred at 100° C. overnight. The reaction mixture was taken up in 1 mL methylene chloride and chromatographed on silica gel with methylen chloride/methanol/triethyl amine 90:10:1. The desired product (181 mg, 47%) was a light yellow solid, MS: m/e=564.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and piperidine in tetrahydrofuran are reacted to give 8-chloro-1-(piperidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:5][C:6](=[O:29])[CH:7]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C=CC(OC)=CC=1)=O.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:5][C:6](=[O:29])[CH:7]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCNC(=O)OCc1ccc(OC)cc1)CSC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O

Procedure:
N-[2-Acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-tryptophane methyl ester (1 g) is dissolved in trifluoroacetic acid (10 ml), the solution is stored at room temperature for fifteen minutes, and then evaporated in vacuo to yield N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester trifluoroacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:18]([BH3-])#N.[Na+].C(O)(=O)C>O.CO>[CH3:18][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: O=C(O)c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(c2ccc(C(=O)O)cc2)CC1
Reaction time: 18 h

Procedure:
A solution of 4-piperidin-4-ylbenzoic acid (0.5 g) and 36% formaldehyde in water (0.175 mL) in methanol (5 mL) was treated with sodium cyanoborohydride (0.13 g) and acetic acid (0.5 mL), stirred for 18 hours and concentrated. The concentrate was flash chromatographed on silica gel with 10% methanol/dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:12].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[Cl:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cc(-c2ccccc2)cc1Cl
Yield: 104.7 %

Procedure:
To a solution of 2,6-dichloro-4-bromobenzoic acid methyl ester (0.55 g) in THF (10 mL) was added benzeneboronic acid (1.30 g), Pd(PPh3)4 (0.16 g) and 2M Na2CO3 (5 mL). The mixture was refluxed for 4 h under N2. After cooling, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane to EtOAc/hexane 1/1) to yield crude 2,6-dichloro-4-phenylbenzoic acid methyl ester (0.57 g). ESMS: m/z 281 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:16]3[C:7]([C:8]4[CH:9]=[C:10]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:11]([C:17]5[CH:22]=[CH:21][C:20]([C:23]6([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]6)=[CH:19][CH:18]=5)=[N:12][C:13]=4[CH:14]=[CH:15]3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[ClH:41].CCOC(C)=O>CO.C(Cl)Cl>[ClH:41].[CH:1]1([C:4]2[N:16]3[C:7]([C:8]4[CH:9]=[C:10]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:11]([C:17]5[CH:22]=[CH:21][C:20]([C:23]6([NH2:27])[CH2:24][CH2:25][CH2:26]6)=[CH:19][CH:18]=5)=[N:12][C:13]=4[CH:14]=[CH:15]3)=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(C6CC6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4ccn5c(C6CC6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl {1-[4-(3-cyclopropyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (MJK-9) (899.4 mg, 18.26 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (4.23 mL, 16.92 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 18 hours the reaction mixture was filtered to give 1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-23) as a yellow solid. HRMS (M+H)+: observed=432.2186, calculated=432.2183.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([Cl:29])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
3-Chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile (1.0 g, 2.3 mmol) was dissolved in methanol (25 mL) and hydrazine monohydrate (0.3 mL, 5.9 mmol) was added. The reaction was stirred for 4 h. Additional hydrazine monohydrate (0.3 mL, 5.9 mmol) was added and stirred overnight. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (0.5 g, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.77 (t, 1H), 7.53 (d, 1H), 7.40 (dd, 1H), 7.32 (t, 1H), 7.19-7.29 (m, 2H), 3.68 (s, 2H), 1.89 (br. s., 2H). MS: m/z 292.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[CH3:8][C:5]1[N:4]=[N:3][C:2]([NH:10][NH2:11])=[CH:7][CH:6]=1
Reactant: NN
Reactant: Cc1ccc(Cl)nn1
Solvent: CCO
Solvent: O
Product: Cc1ccc(NN)nn1
Yield: 80 %

Procedure:
To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin-3-yl)-hydrazine was obtained as a white crystalline solid (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[H-].[Na+].Cl[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:32][C:33]#[N:34])[C:6]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cc3cc(Cl)ccc3n2CC#N)CC1
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a stirred solution of 40 mg (0.10 mmol) of (5-chloro-1H-indol-2-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone in DMF (3 ml) at RT was added 5 mg (0.11 mmol) of NaH (in oil, 55%). After 20 minutes, 8 mg (0.10 mmol) of chloro-acetonitrile was added and stirring was continued over night. The reaction mixture was concentrated in vacuo and purification by preparative HPLC (30% CH3CN/H2O) afforded 9 mg (18%) of {5-chloro-2-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].O>C1(C)C=CC=CC=1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:18](=[O:19])[CH2:17][Cl:16])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: O=C(CCl)c1c[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 23.7 %

Procedure:
To a stirred solution of 6.00 g (51.2 mmole) indole and 4.2 ml (47.5 mmole) pyridine in 50 ml toluene at 55° C. was added dropwise 5.85 g (51.8 mmole) chloroacetyl chloride. The resulting orange-colored mixture was stirred at 55° C. for 90 minutes and cooled to room temperature. Water (150 ml) and methanol (25 ml) were added and the mixture stirred for another hour. The precipitate was collected, washed with water (50 ml) and dried to give 10.18 g of crude product. This was triturated with chloroform, filtered, the solid washed with chloroform and crystallized from methanol to afford 2.35 g (23%) of product; m.p. 236°-237° C. Reworking the mother liquors gave a second crop which was purified by flash chromatography on silica gel. Two recrystallizations of this product gave an analytically pure product; m.p. 236°-237° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH2:18][CH3:19])[CH:11]=2)=[CH:28][CH:29]=1
Reactant: Nc1ccncc1
Reactant: CCc1cc(C(=O)O)ccc1OCC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCc1cc(C(=O)Nc2ccncc2)ccc1OCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 23-6 (270 mg, 1.0 mmol) in 3.6 mL of CH2Cl2 was added 0.13 mL (1.5 mmol) of oxalyl chloride. The resulting solution was stirred for 1 h, cooled to 0° C. and treated with 380 mg (4.0 mmol) of 4-aminopyridine. Stirring was continued for 1 h before the heterogeneous mixture was diluted with CH2Cl2 and quenched with sat'd NaHCO3. The organic extract was washed with water, brine and dried over Na2SO4. Evaporation of the solvent and column chromatography (3:1 EtOAc/Hexane) afforded product 23-7.
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=C.C(OC(N[C@H](C(O)=O)CCCC)=O)C=C>>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Agent: C=CCOC(=O)N[C@@H](CCCC)C(=O)O
Product: C=CCCOC(=O)N[C@@H](CCCC)C(=O)O

Procedure:
The title compound was prepared in a manner similar to Example 1 (Steps 1-8). N-[(but-3-en-1-yloxy)carbonyl]-L-norleucine was prepared according to the procedure used for [(4-pentenyloxy)carbonyl]-L-norleucine (Example 3), and was used in place of N-[(allyloxy)carbonyl]-L-norleucine. 1H NMR (500 MHz, MeOH-d4) ppm: 8.58 (s, 1H), 8.42 (s, 1H), 8.09 (m, 3H), 7.96 (d, 1H), 7.74 (m, 4H), 6.70 (d, J=15.2 Hz, 1H), 6.39 (m, 1H), 5.87 (m, 2H), 5.29 (d, 1H), 5.10 (d, 1H), 4.80 (m, 2H), 4.71 (m, 2H), 4.57 (t, 1H), 4.07 (m, 2H), 2.86 (dd, 1H), 2.70 (m, 1H), 2.55 (m, 1H), 2.48 (t, 1H), 2.17 (dd, 1H), 1.85 (m, 1H), 1.79-1.64 (m, 2H), 1.55-1.37 (m, 5H), 1.01 (t, 3H). LRMS (CI, [M+H]) Calc'd=653.4. found=653.4.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([Mg]Br)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>C1COCC1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:12][CH:11]=2)=[O:9])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(OC)c3)sc2c1
Yield: 66.2 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.64 g, 3.75 mmol) in THF (15 mL) was treated with a 0.63 M solution of 3,4-dimethoxyphenylmagnesium bromide (12.0 mL, 7.56 mmol) (prepared from 4-bromoveratrole, catalytic iodine, and magnesium turnings in THF). Purification by chromatography (silica gel, 5-10% MeOH in CH2Cl2) gave 1.32 g (66%) of the title compound as a yellow foam: 1H NMR d 1.45 (m, 2H), 1.61 (m, 4H), 2.48 (m, 4H), 2.75 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 4.09 (t, J=6.0 Hz, 2H), 6.76 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.7 Hz, 2H), 6.91 (d, J=1.6 Hz, 1H), 6.98 (dd, J=2.2 Hz, 8.9 Hz, 1H), 7.04 (dd, J=1.6 Hz, 8.2 Hz, 1H), 7.33 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H); 13C NMR d 23.6, 25.3, 54.5, 55.1, 55.2, 55.3, 57.1, 65.6, 104.0, 110.6, 111.6, 113.7, 114.3, 121.0, 123.5, 125.7, 129.9, 130.1, 131.7, 133.4, 139.5, 141.8, 148.1, 148.7, 157.2, 162.5, 192.8; MS (FD) m/e 531 (M+); Anal. calc'd. for C31H33NO5S: C, 70.03; H, 6.26; N, 2.63. Found: C, 70.21; H, 6.36; N, 2.67.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[N:16][CH:15]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:13]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[CH:17]=[N:16][CH:15]=[C:14]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C)n(-c2cncc(Cl)n2)n1
Reactant: Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)n(-c2cncc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 161 mg, 4.03 mmol) was added to a suspension of 4-chloroaniline (489 mg, 3.83 mmol) in dimethylsulfoxide (10 mL). The mixture was stirred at 130° C. for 5 minutes. 2-Chloro-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazine was added and the resulting mixture was stirred at 130° C. for 30 minutes. Cooling, followed by addition of water gave a brown precipitate. The brown solid was collected by filtration, re-dissolved in ethyl acetate, washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by flash chromatography to give (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-amine (318 mg, 55%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[C:40]([C:44]1[CH:48]=[CH:47][N:46]([C:49]2[CH:54]=[C:53]([Cl:55])[CH:52]=[CH:51][C:50]=2[C@@H:56]([OH:61])[C:57]([F:60])([F:59])[F:58])[N:45]=1)([CH3:43])([CH3:42])[CH3:41]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:61][C@H:56]([C:50]2[CH:51]=[CH:52][C:53]([Cl:55])=[CH:54][C:49]=2[N:46]2[CH:47]=[CH:48][C:44]([C:40]([CH3:43])([CH3:41])[CH3:42])=[N:45]2)[C:57]([F:59])([F:60])[F:58])[N:3]=1
Reactant: CC(C)(C)c1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: CC(C)(C)c1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 40).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.OS(O)(=O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 130 °C
Yield: 98 %

Procedure:
To a hot solution of 2-amino-5-nitropyridine (1.4 g, 10 mmol) in acetic anhydride (5 mL) at 100° C. was added conc. H2SO4 (0.1 mL). The resulting mixture was heated at 130° C. for 2 h, cooled and partitioned between EtOAc (200 mL) and water (100 mL). The layers were separated and the aqueous layer was washed once with EtOAc (100 mL). The combined organic layers were washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and then brine (50 mL); dried over anhydrous MgSO4 and concentrated under reduced pressure to afford N-(5-nitropyridin-2-yl)acetamide (1.8 g, 98%), which was used without further purification. 1H-NMR-(CDCl3): δ 9.14 (1H, d), 8.50 (1H, dd), 8.40 (1H, d), 8.23 (1H, br s), 2.29 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[Cl:83]C1C=C(B(O)O)C=C(Cl)C=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[C:42]([Cl:83])[CH:43]=[C:2]([Cl:1])[CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cc(Cl)cc(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 15 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3,5-dichlorophenylboronic acid (50 mg, 0.2625 mmol) to produce the title compound (17 mg, 15% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10](O)([CH3:12])[CH3:11])[C:7]([NH:14][CH:15]=O)=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26]>CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])[N:14]=[CH:15][CH:11]=[C:10]2[CH3:12])=[O:27]
Reactant: COC(=O)c1cc(C(C)(C)O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)ccnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 160 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(4-bromo-2-fluorophenylamino)-3-fluoro-4-formylamino-5-(1-hydroxy-1-methyl-ethyl)-benzoic acid methyl ester (1.00 equiv.) and polyphosphoric acid is stirred at 160° C. for 20 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to yield the desired product as necessary.