Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[C:12]([C:28]4[NH:32][N:31]=NN=4)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Cl:33][CH2:34][C:35]1[O:36][C:28]([C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[N:32][N:31]=1
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnn[nH]3)cc(-c3cccc4[nH]ccc34)cc21
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 100 °C
Yield: 15.2 %

Procedure:
6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-4-(1H-tetrazol-5-yl)-1H-indazole (1.41 g, 3.19 mmol) was slurried into anhydrous chloroform (20 ml), treated with chloroacetyl chloride (1.023 ml, 12.78 mmol) and heated at 100° C. in a Biotage Initiator microwave for 30 mins, the mixture was split into 4 batches for the microwave reaction. The mixtures were allowed to cool to room temperature and the resultant precipitate collected by filtration to give the title compound as a yellow/brown solid (0.237 g). LCMS (Method A): Rt 1.25 mins, MH+490.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(Oc2ccccc2)nn1
Temperature: 25 °C

Procedure:
3,6-Dichloropyridazine (Aldrich, 4.47 g, 30 mmol) in NaOH (10%, 20 mL) was treated with phenol (Aldrich, 1.88 g, 20 mmol) at 100° C. for 15 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, Hexanes: ethyl acetate=80: 20, Rf. 0.5) as a solid (3.8 g, yield, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.11–7.29 (m, 3H), 7.38–7.55 (m, 4H) ppm. MS (DCl/NH3) m/z 207 (M+H)+, 209 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Li]CCCC.[I:20]I>C1COCC1>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([I:20])[CH:6]=1
Reactant: II
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(I)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 5-(3,3-Dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (6.2 g, 30 mmol; see patent application U.S. Pat. No. 5,861,421) in THF (100 mL) was added a solution of nBuLi (2.0 M in pentane, 33 mL, 66 mmol) via an addition funnel at −78° C. After addition, the reaction was stirred at −78° C. for 1 h. A solution of I2 (7.7 g, 30 mmol) in THF (100 mL) was added slowly (ca. 15 min) to the flask. After a further 10 mins, the reaction was quenched with 1 N HCl (50 mL) and warmed to room temperature. The volatiles were removed in vacuo and the residue was dissolved in ether (500 mL). The organic solution was washed with 1 M Na2S2O3 (100 mL×2), brine (100 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by silica gel chromatography (EtOAc/hexanes) to give 5-(3,3-Dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid (5.9 g, 65%) as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[CH:7]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[N:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C=O)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1>O>[C:1]([NH:5][C:6](=[O:32])[CH:7]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[NH:8][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C(c1c(C(=O)O)[nH]c2cc(Cl)ccc12)N(C=O)Cc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NC(=O)C(NCc1ccc(Cl)cc1)c1c(C(=O)O)[nH]c2cc(Cl)ccc12
Yield: 89.2 %

Procedure:
Compound 9l (24 mg, 0.05 mmol) was treated with 0.4 mL of dioxane (2M HCl), 0.1 mL of water stirring overnight under 60° C. After evaporation, the product was obtained as yellow solids (20 mg, yield: 89%). HPLC/MS: tR=10.42 min; m/z=448.3 [M+H]+ HRMS: C22H22Cl2N3O3, [M−H]−; 446.1038 (calcd.), 446.1050 (found). 1H NMR (600 MHz, MeOD, a mixture of rotamers): 1.25 (s, 9H), 1.31 (s, 6H), 4.27-4.33 (m, 2H), 4.70 (ABd, 1H, J=16.2 Hz), 5.13 (ABd, 1H, J=15.6 Hz), 5.88 (s, 1H), 6.24 (s, 1H), 6.47 (m, 1H), 6.76-7.27 (m, 8H), 7.39-7.60 (m, 6H), 7.79-7.85 (m, 2H), 8.38 (s, 1H), 8.47 (s, 1H), 11.35 (s, 1H), 11.60 (s, 1H). 13C NMR (150 MHz, MeOD, a mixture of rotamers): 27.3, 27.4, 46.5, 50.9, 51.0, 57.1, 111.6, 120.4, 121.3, 125.0, 126.8, 127.3, 127.5, 127.9, 128.6, 128.9, 129.0, 129.6, 131.0, 132.1, 135.3, 135.5, 170.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)cc1

Procedure:
69 mg of pale yellow solid 3-{4-[3-(3-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-fluoro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([C:32]4[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=4)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NCC1(c2cccnc2)CCCCC1)c1sc(Br)nc1C(F)(F)F
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: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)c(C(=O)NCC3(c4cccnc4)CCCCC3)s2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (44.8 mg), 2-methoxy-5-pyridineboronic acid (30.6 mg), Pd(PPh3)4 (5.8 mg) and Na2CO3 (42.4 mg) in dioxane (2 mL) and water (0.8 mL) is heated at 110° C. in an argon purged sealed vial for 2 h. The mixture is poured into water and extracted with EtOAc. The extract is concentrated and the residue is purified by PTLC (silica gel, 5% MeOH in methylene chloride) to give the title compound. MS (M+1)=477.19; RT=1.19 min. *IC50.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH:25]([CH3:37])[CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:23][N:24]([CH3:38])[CH:25]([CH3:37])[CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(N)cc1OCC(C)N(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCC(C)N(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-dimethylaminopropoxy)-4-methoxyaniline (D7) using a similar procedure to Example 1 (34%) mp 105°-110° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]([CH:16]=O)[NH:11][C:12]([O:14][CH3:15])=[O:13].C([O-])(=O)C.[NH4+].C([NH2:26])=O.C(#N)C>O>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:26]=[CH:16][N:10]([NH:11][C:12](=[O:13])[O:14][CH3:15])[CH:9]=1
Reactant: NC=O
Reactant: COC(=O)NN(C=O)CC(=O)c1cnn(C)c1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Nn1cnc(-c2cnn(C)c2Br)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-[2-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-oxoethyl]-2-formylhydrazine carboxylate (1.20 g, 3.76 mmol) was mixed with ammonium acetate (1.16 g, 15.0 mmol), formamide (4 mL) and acetonitrile (5 mL). The reaction was heated to 130° C., and the acetonitrile was allowed to boil off for 10 minutes. Heating was continued for an additional 4 hours. After addition of water, the crude mixture was extracted eight times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 100% [10% methanol in ethyl acetate] in heptane) afforded the product as a pinkish solid. Yield: 800 mg, 2.67 mmol, 19% over two steps. LCMS m/z 299.8 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.80 (br s, 3H), 3.90 (s, 3H), 7.52 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[C@H:27]([OH:33])[CH2:26]1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Temperature: 40 °C
Yield: 58.1 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 27C, 2.35 g, 8.42 mmol) in dichloromethane (15 mL) was added at room temperature to a suspension of (S)-6-((S)-3-amino-4-hydroxy-butyl)-6-aza-spiro[2.5]octan-4-ol (1.81 g, 8.42 mmol), sodium triacetoxyborohyride (2.21 g, 1.01 mmol) and acetic acid (1.01 g, 16.8 mmol) in dichloromethane (15 mL). The reaction mixture was heated at 40° C. for 72 h, then partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (2.18 g, 58%). White foam, MS (ISP)=446.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20].O>CN(C=O)C>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:18])[CH3:1])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[C:19]=[S:20]
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Dimethyl-[1-(4-nitro-phenyl)-piperidin-4-yl]-amine (Example 2, 1.1 g, 5.0 mmol) was dissolved in DMF (5 mL). To the stirred solution, thiocarbonyl diimidazole (Aldrich, 1.18 g, 90%, 6 mmol) was added and the solution was stirred at room temperature for 80 minutes. The mixture was poured into water and extracted with diethyl ether. The extract was dried with sodium sulfate and concentrated to give a pale yellow solid. 1.12 g, 85%. MS (m+H)+: 262.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH3:37]>C(Cl)Cl>[CH3:37][CH:32]1[N:31]([CH3:30])[CH2:36][CH2:35][N:34]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:29][CH:28]=2)[CH2:33]1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC1CNCCN1C
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmole) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H), 4.65 (m, 1H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H), 7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH:7]([Cl:30])[C:8]([NH:10][C:11]1[N:15]([C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[C:18]([F:28])[C:17]=2[F:29])[N:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[Cl:4][C:12]1[CH:13]=[N:14][N:15]([C:16]2[C:17]([F:29])=[C:18]([F:28])[C:19]([C:24]([F:27])([F:26])[F:25])=[C:20]([F:23])[C:21]=2[F:22])[C:11]=1[NH:10][C:8](=[O:9])[CH:7]([Cl:6])[Cl:30]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F)C(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F)C(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
0.9 ml (0.011 mol) of sulphuryl chloride in 5 ml of methylene chloride are added dropwise to a solution of 4.1 g (0.01 mol) of 5-dichloroacetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of methylene chloride at 0° C.-5° C. The mixture is stirred at room temperature for 16 hours and diluted with 30 ml of methylene chloride, the solution is washed with saturated sodium bicarbonate solution and sodium chloride solution in succession and dried over magnesium sulphate and the solvent is removed in vacuo. 3.9 g (87.2% of theory) of 4-chloro-5-dichloroacetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 115° C.-116° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
3-Nitro-1-iso-butyl-1H-pyrazole (83 mg, 0.49 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-butyl-1H-pyrazol-3-ylamine (59 mg, 86%) as a golden oil: ESI-LRMS m/e calcd for C7H13N3 [M+] 139.1, found 140.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)C(=O)O
Reactant: NCc1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (200 mg, 1.069 mmol), isobutyric acid (0.159 mL, 1.711 mmol), BOP-reagent (757 mg, 1.711 mmol) and diisopropylethylamine (0.747 mL, 4.28 mmol) in DMF (6 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)isobutyramide (230 mg, 0.894 mmol, 84% yield) as an orange oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.42 (s, 2H), 2.53 (dt, J=13.8, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 6H). MS (ES+) m/z: 257.0, 259.0 (M+H); LC retention time: 1.200 min (analytical HPLC Method O).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.F[C:22]1C=C(C(O)(C)C)C=C(F)C=1>>[F:17][C:6]1[CH:5]=[C:4]([C:18]([OH:20])([CH3:22])[CH3:19])[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Product: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 2-(3,5-difluorophenyl)propan-2-ol (see US2012/225062) provided the title compound.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=O.[OH-].[Na+]>Cl>[OH:13][C:14]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:18])[CH3:15]
Reactant: CC(C)(O)C(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.5 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (1.5 g, 9.2 mmol) in 4 M HCl (50 mL) was added 2-hydroxyisobutyric acid (2.87 g, 27.6 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH ˜3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. The filtrate was concentrated and the residue was rinsed with ether. The remaining solid residue was dissolved in ethyl acetate, and washed with brine solution. After drying over MgSO4, the organic solution was evaporated in vacuo, yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09. found 221.1. 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1H), 7.7 (dd, 1H), 7.2 (m, 1H), 1.3 (s, 6H).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].CCCCCC>C1COCC1>[CH3:27][S:28]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)(=[O:30])=[O:29]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 7.7 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2 g, 7.78 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.8 M in THF, 8.8 mL, 15.56 mmol) and was stirred at the same temperature for 45 minutes followed by addition of methanesulfonyl chloride (1.3 g, 11.67 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 30% EtOAc:hexane to obtain the product as an orange viscous liquid (0.20 g, 8.0% yield). MS: 336.18 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:11])[F:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:10])[F:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=C(F)F)C4CCCC4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4-[1-(1-cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the desired product (39 mg, 98%).