Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH:13]=[CH:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:11]=2)[C:18]=1[C:21]#[N:22]
Reactant: CSC(Nc1cccc(CNC(=O)OC(C)(C)C)c1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(Nc2n[nH]c(N)c2C#N)c1

Procedure:
A mixture of 145.4 g (422 mmol) of 3-[3-(N-Boc-aminomethyl)-phenylamino]-2-cyano-3-methylmercapto-acrylonitrile, 21.96 ml (443 mmol) of hydrazine hydrate and 1000 ml of methanol is heated under reflux for 2 hours and then concentrated by evaporation in vacuo, yielding 5-amino-[3(N-Boc-aminomethyl)-phenylamino]4-cyano-pyrazole; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
To a solution of 4-(2-Hydroxyethyl)phenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol). The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL), and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the 2.69 g (99%) of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:5].[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: Nc1ccc(Oc2ccccc2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)c(Cl)c1
Yield: 70 %

Procedure:
Proceeding as in Reference 5, but substituting 3-chloro-4-phenoxyaniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(3-chloro-4-phenoxyphenyl)propanamide (470 mg, 70%).
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[C:3]1[O:8][C:7](=[C:9]([Cl:11])[Cl:10])[C:6]2[CH:12]=[C:13]([C:16]([NH2:18])=O)[CH:14]=[CH:15][C:5]=2[O:4]1.S(Cl)(Cl)=O>CN(C)C=O>[C:16]([C:13]1[CH:14]=[CH:15][C:5]2[O:4][C:3](=[C:2]([Cl:19])[Cl:1])[O:8][C:7](=[C:9]([Cl:11])[Cl:10])[C:6]=2[CH:12]=1)#[N:18]
Reactant: NC(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(=C(Cl)Cl)O2
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=C(Cl)Cl)OC(=C(Cl)Cl)O2
Temperature: 25 °C

Procedure:
2,4-Bis(dichloromethylene)benzo[1,3]dioxin-6-carboxamide (3.0 g.) was added in portions to a stirred mixture of thionyl chloride (15 ml.) in dimethylformamide (60 ml.) at 50° C. A precipitate rapidly formed which, after cooling the reaction mixture to ambient temperature, was filtered off, dried, and crystallised from ethanol to give 6-cyano-2,4-bis(dichloromethylene)benzo[1,3]dioxin, m.p. 167°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.COC(=O)C1C=CC(N)=C([O:87][C:88]([F:91])([F:90])[F:89])C=1>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([O:87][C:88]([F:91])([F:90])[F:89])[CH:10]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1ccc(N)c(OC(F)(F)F)c1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(OC(F)(F)F)c1
Yield: 85 %

Procedure:
This compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c), 4-amino-3-trifluoromethoxy-benzoic acid methyl ester and using pyridine as a base to afford the title compound as a colorless solid (85%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:20][CH:5]2[CH:4]([N:1]=[N+:2]=[N-:3])[CH2:10][CH2:9][N:8]([C:11]3[N:15]([CH3:16])[N:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCN(c3c([N+](=O)[O-])cnn3C)CCC2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (4.0 g, 14.2 mmol) in dry DCM (100 mL) cooled to 0° C. was added slowly triethylamine (4.0 mL, 28.5 mmol) followed by DMAP (175 mg, 1.42 mmol) and 4-methylbenzene-1-sulfonyl chloride (4.1 g, 21.4 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. More 4-methylbenzene-1-sulfonyl chloride (1.4 g, 7.12 mmol) was added to the reaction mixture, which was stirred at room temperature for a further 24 hr. Water (40 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (30-70% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl 4-methylbenzenesulfonate as a dark cream solid (2.81 g). This solid (2.3 g, 5.29 mmol) was treated with a solution of TBAF (1.0 M in THF, 21 mL, 21.1 mmol) and the reaction mixture was heated at 60° C. for 2 hr. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (30-40% EtOAc/isohexane) gave 4-azido-5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow viscous oil (804 mg, 20% over two steps) 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.06 (ddt, J=46.2, 8.1, 2.5 Hz, 1H), 4.00 (dd, J=20.8, 8.1 Hz, 1H), 3.79 (s, 3H), 3.43-3.34 (m, 2H), 3.26-3.11 (m, 2H), 2.43-2.30 (m, 1H), 2.30-2.18 (m, 1H), 2.12-1.92 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[N:28][CH:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:27]=[N:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.6 g, 6.4 mmol) in anhydrous DMF (15 mL) was added cesium carbonate (5.2 g, 16.0 mmol) and 6-chloro-pyrazine-2-carbonitrile (0.89 g, 6.4 mmol). The resulting mixture was stirred at room temperature overnight then quenched with crushed ice. The pH was adjusted to 2 with 6M HCl and the mixture extracted with EtOAc (2×200 mL). The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-75% EtOAc in hexane) to give 6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.6 g, 71%). 1H NMR 400 MHz (DMSO-d6) δ 9.30 (s, 1H), 8.93 (s, 1H), 8.90 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 5.58 (m, 1H), 4.05 (q, J=7.2, 2H), 3.17 (m, 1H), 2.40 (m, 1H), 2.33 (s, 3H), 1.13 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:29][CH2:28][CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH:7]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)cc2Cl)cc1
Product: NC(=O)c1ccc(Oc2ncc(CNCCc3cccc(Cl)c3)cc2Cl)cc1
Yield: 37.5 %

Procedure:
Using a method similar to Example 462, using 4-(3-chloro-5-formyl-pyridin-2-yloxy)-benzamide (101 mg, 0.365 mmol) and 2-(3-chloro-phenyl)-ethylamine (0.056 mL, 0.402 mmol) gives the title compound (57 mg, 36%). Mass spectrum (ion spray): m/z=415.9 (M+1); 1H NMR (CDCl3): 7.93 (d, J=1.7 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.77 (d, J=1.7 Hz, 1H), 7.22-7.17 (m, 4H), 7.07 (d, J=7.0 Hz, 1H), 6.12 (bs, 2H), 3.74 (s, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 1.42 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:10]=2)=[CH:4][CH:3]=1.Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[N:12]=[C:11]([N:21]3[CH2:22][CH2:23][N:24]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:25][CH2:26]3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCNCC3)n2)cc1
Reactant: Cc1cccnc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4ncccc4C)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of N-(4-methylphenyl)-2-(1-piperazinyl)-6-(1-piperidinyl)-4-pyrimidinamine (100 mg, 0.284 mmol), 2-bromo-3-methylpyridine (54 mg, 0.312 mmol), 1,1′-(bisdiphenylphosphino)-1,1′-binaphthol (13 mg), tris(dibenzylidene acetone)dipalladium(0) (13 mg), and sodium tert-butoxide (136 mg) in dry toluene (4 mL) was heated at 90° C. in a sealed tube for 2 hours. The reaction was quenched with water and the solution was extracted three times with ethyl acetate. The solvent was dried and removed. The crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (2:1). N-(4-methylphenyl)-2-[4-(3-methyl-2-pyridinyl)-1-piperazinyl]-6-(1-piperidinyl)-4-pyrimidinamine was obtained, from the band at Rf=0.46, as a solid (17.1 mg, 0.0385 mmol, 14%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of 2.0 g (10.4 mmol) of 7-nitro-1,2,3,4-tetrahydro-1-naphthylamine in 35 ml of THF was treated with ice-cooling with 4.2 g (41.6 mmol) of triethylamine and 1.3 g (11.4 mmol) of methanesulfonyl chloride and then stirred at RT for 2 hrs. After addition of 20 ml of water, the mixture was concentrated in vacuo down to a 10 ml residue, then treated with a further 20 ml of water, and the precipitated product was filtered off with suction. After drying in vacuo, 2.5 g of N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide were obtained; m.p. 150-152° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=4[O:37][CH3:38])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:39])[N:15]=1)=[O:13])[CH3:2].[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:24]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]4[C:14]([C:12]([NH:11][C:4]5[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][CH3:2])=[O:13])=[N:15][N:16]([CH3:39])[C:17]=4[C:26]=3[N:25]=2)=[C:29]([O:37][CH3:38])[CH:30]=1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc([N+](=O)[O-])cc3OC)nc1-2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(N)cc3OC)nc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2,6-diethylphenyl)-8-[(2-methoxy-4-nitrophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (1.4 g, 2.656 mmol) in 27 ml of dioxane, zinc (695 mg, 10.624 mmol) and ammonium chloride (1.4 g, 26.56 mmol) in 2.7 ml of water were added and heated at 100° C. under stirring for 8 h. The mixture was cooled, the insoluble material filtered off and washed with ethyl acetate, the combined organic solutions are washed with aqueous citric acid solution, dried on Na2SO4 and evaporated in vacuo leaving a pink foam as crude title product that has been used without any further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 70 %

Procedure:
2-(3-Bromoimidazo[1,2-a]pyrimidin-7-yl)propan-2-ol was coupled with 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 4-fluoro-3′-[7-(2-hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (260 mg, 70%) as a yellow powder: δH (360 MHz, CDCl3) 1.61 (6H, s), 4.51 (1H, s), 7.07 (1H, d, J 7), 7.45 (1H, ddd, J 8, 1 and 1), 7.51-7.60 (3H, m), 7.63-7.69 (2H, m), 7.73 (1H, s), 7.90 (1H, s), 8.94 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:25][C:26]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1)=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:39][C:38]1[CH:37]=[CH:36][C:24]([CH2:25][C:26]2([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:28][CH2:27]2)=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC([C@H](N)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Reaction time: 8 h

Procedure:
5.31 g (9.61 mmol) of tert-butyl 1-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorobenzyl]cyclopropanecarboxylate (Example 32A, racemic diastereomer mixture) were dissolved in a mixture of 100 ml of ethanol and 20 ml of THF. The solution was inertized with argon, and 511 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with ethanol/THF, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→4:1) and the diastereomers were separated:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:3][CH2:2]1.C1COCC1>[Pd].CO>[F:33][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2ccc(C3=CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2ccc(C3CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 1-[4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (300 mg, 0.675 mmol), 10% Pd—C (50% wet, 300 mg), THF (30 mL), and MeOH (30 mL) was hydrogenated for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH/H2O to give the title compound (255 mg, 85% yield) as a white solid: mp 187-189° C.; 1H NMR (300 MHz, CDCl3): δ ppm 1.57-1.83 (4H, m), 2.72-2.82 (1H, m), 3.45-3.58 (2H, m), 3.90 (3H, s), 4.09 (2H, td, J=3.0, 11.3 Hz), 6.35 (1H, t, J=8.3 Hz), 6.86 (1H, dd, J=1.5, 8.3 Hz), 7.03 (1H, dd, J=1.9, 12.8 Hz), 7.28 (1H, d, J=1.9 Hz), 7.35-7.46 (5H, m), 7.78 (1H, d, J=1.9 Hz), 7.79 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C25H23FN4O3: C, 67.25; H, 5.19; N, 12.55. Found: C, 67.13H, 5.13; N, 12.57.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:12])[CH3:11]>C(O)(=O)C>[CH3:11][C:10]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[O:12]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1c(Cl)cccc1Cl
Temperature: 90 °C

Procedure:
To a mechanically stirred solution of 2,6-dichloroaniline (76 g, 0.047 mol) in 60 mL of glacial acetic acid is added dropwise acetyl chloride (36 mL, 0.5 mol). After the addition is complete, the reaction mixture is heated at 90° C. for 20 minutes. The solution is poured into ice water (500 mL), forming a white precipitate. The solids are filtered, washed with water and dried to give the product (91.8 g, 96%, white solid, m.p. 179°-180° C., lit. m.p. 180°-181° C. form glacial acetic acid).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.[CH3:11][C:12]1([C:19]([O:21][CH3:22])=[O:20])CC2C[CH:13]1C=C2.C1CC=CC=1.COC1C=CC(O)=CC=1>C(OC)(=O)C(C)=C>[CH3:11][C:12]1([C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH:1]2[CH2:2][CH:3]1[CH:4]1[CH:5]2[CH:6]2[CH2:7][CH:8]1[CH:9]=[CH:10]2
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: COC(=O)C1(C)CC2C=CC1C2
Agent: C1=CCC=C1
Agent: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Product: COC(=O)C1(C)CC2CC1C1C3C=CC(C3)C21
Temperature: 180 °C

Procedure:
A 50 liter reaction vessel equipped with a stirrer maintained at a temperature of 180° C. and pressure of 3.5 kg/cm2.G was continuously charged with a mixture of methyl methacrylate, dicyclopentadiene, and 5-methyl-5-methoxycarbonylbicyclo[2.2.1]hept-2-ene, at a ratio of 1:2.4 (cyclopentadiene base):2.4, at a feed rate of 4 kg/hour, so that the average residence time of the reaction raw materials in the reaction vessel was maintained 8 hours. As a polymerization inhibitor, a solution of p-methoxyphenol in methyl methacrylate was added in an amount of 300 ppm (weight base) of the total amount of the reaction raw materials.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:3]([NH:5][C@@H:6]([CH3:20])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:4].[Cl:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH:1][C@@H:2]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:3]([NH:5][C@@H:6]([CH3:20])[CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=2)=[O:4])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](N)CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CC1CCCCC1)NS(=O)(=O)c1cccc(Cl)c1
Reaction time: 12 h

Procedure:
The product from step D (15.4 mg, 39.7 μmol) was added to a flask with DMAP (14.5 mg, 0.119 mmol) and dry DMF (0.5 mL). 3-Chloro-benzenesulfonyl chloride (8.37 mg, 39.7 μmol) was added as a solution in 0.5 mL of dry DMF dropwise over 3 minutes. The resulting solution was stirred for 12 hours and the volatiles were stripped off. The solids were taken up in methanol and purified by prep HPLC. Yield 15 mg, 67%. 1H NMR (CDCl3) δ(ppm): 7.9 (s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.6 (d, J=8 Hz, 1H), 7.5 (t, J=7.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 6.6 (d, J=8.9 Hz, 2H), 6.15 (s, 1H), 5.1 (s, 1H), 4.1 (m, 1H), 3.65 (m, 1H), 3.25 (dd J=4.7, 12.9 Hz, 1H), 3.1 (dd J=7.5, 12.7 Hz, 1H), 1.6 (m, 7H), 1.4 (m, 1H), 1.3 (m, 1H), 1.2 (d, J=8.4 Hz, 3H), 1.07 (m, 3H), 0.65 (m, 1H). C25H31CWF3N3O4S: LC/MS=562.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=O)[N:8]([CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.N.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:9]1[N:8]([CH3:13])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c1[nH]c(=O)n2C
Agent: N
Product: COc1cccc2c1nc(Cl)n2C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3.7 g 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one are suspended in 15 ml phosphorus oxychloride. The reaction mixture is stirred for 3 hours at reflux temperature, slowly combined with ice water and made alkaline with conc. ammonia. The precipitated product is suction filtered. 3.6 g product are obtained as a solid. M.p=118-119° C.
Reaction SMILES: C([O-])(O)=O.[Na+:5].[O-]S([O-])=O.[Na+].[Na+].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1>O>[Na+:5].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1cccnc1
Temperature: 80 °C

Procedure:
To a solution of 0.39 g of NaHCO3 (4.6 mmol) and 0.58 g of Na2SO3 (4.6 mmol) in water (2.5 mL) were added 0.5 g (2.3 mmol) of 3-pyridinesulfonyl chloride. The reaction was heated at 80° C. for 3 h. The solvent was removed under reduced pressure. The filtrate was concentrated under reduced pressure to give 3-pyridylsulfinic acid sodium salt.