Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[O:22])[C@@H:17]2[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[O:22])[C@@H:17]2[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH:12]=[CH:11][N:10]=1
Reactant: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)[C@H]1C(=O)NS(C)(=O)=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N)c2)[C@H]1C(=O)NS(C)(=O)=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 95 in 1 mL dichloromethane was added 300 uL of TFA. The reaction was stirred for 1 hour and then concentrated in vacuo. The crude material was purified via reverse phase HPLC (C18, acetonitrile/water with 0.1% TFA) to yield 0.75 mg of 96. MS [M+H]+=446.0
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[N:20][CH:21]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and cyclopropanamine (11.15 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 41.2 mg (50%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.81 (s, 1H), 9.85 (br. s., 1H), 8.61 (d, J=2.3 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 8.01 (dd, J=9.0, 2.4 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.42-4.64 (m, 3H), 4.24 (br. s., 2H), 3.92-4.01 (m, 1H), 3.42 (br. s., 2H), 2.94-3.26 (m, 4H), 2.75-2.86 (m, 1H), 2.58-2.73 (m, 1H), 2.03-2.12 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.6 Hz, 1H), 1.31-1.61 (m, 3H), 0.62-0.73 (m, 2H), 0.46-0.57 (m, 2H). [M+H] calc'd for C, 25; H, 31; N, 7; O, 2, 462; found, 462.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([F:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2sc(F)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(F)sc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>C1COCC1>[CH3:35][N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][NH:23][C:21]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[N:22]=2)[CH2:26]1
Reactant: c1cnc2c(NCC3CCCNC3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
A solution of 7-(4-morpholinophenyl)-N-(piperidin-3-ylmethyl)pyrido[4,3-b]pyrazin-5-amine (Compound 3, 40 mg, 0.1 mmol) and formaldehyde (60 mg, 2.0 mmol), NaBH(OAc)3 (25 mg, 0.15 mmol) in THF (20 mL) was stirred at ambient temperature overnight, then concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound. MS (m/z): 419 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([NH2:9])[C:7](=[O:10])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:4]=1)[CH3:2].[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>CC(C)=O>[CH2:1]([C:3]1[N:8]([N:9]=[CH:18][CH2:17][CH3:22])[C:7](=[O:10])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1nnc(-c2ccccc2)c(=O)n1N
Solvent: CC(C)=O
Product: CCC=Nn1c(CC)nnc(-c2ccccc2)c1=O
Yield: 7323.4 %

Procedure:
10.8 g (0.05 mole) of 3-ethyl-4-amino-6-phenyl-5H-1,2,4-triazin-5-one (known from DOS (German Published Specification) 2,138,031) were dissolved in 250 ml of acetone and after addition of 0.1 g of p-toluenesulphonic acid the mixture was heated to the boil under reflux for 1 hour. The reaction solution was filtered hot, the solvent was then partly distilled off and 20 to 50 ml of isopropanol were added to the residue. The crystalline precipitate thereupon obtained was filtered off and washed with ether. 10.9 g (85% of theory) of 3-ethyl-4-propylideneamino-6-phenyl-5-H-1,2,4-triazin-5-one of melting point 146°C were thus obtained.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:43]([CH3:44])=[CH:42][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[N:35]=[CH:34]5)[C:26]3=[O:41])[S:24][C:20]=2[C:19]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:43]([CH3:44])=[CH:42][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[N:35]=[CH:34]5)[C:26]3=[O:41])[S:24][C:20]=2[C:19]=1[C:45]1[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
. A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O, 114 mL). To a solution of (S)-1-(6-(1-tert-butoxy-2-hydroxyethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-3-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one (16 mg) in wet acetonitrile (1.0 mL, 0.75% H2O) at 0° C. was added the above stock solution (0.6 mL) at 0° C. Filtration and purification by reverse phase HPLC gave (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C32H32ClN5O4S: 618.2 (M+H+); Found: 618.3 (M+H+), 615.8 (M+H+); 1H-NMR 400 MHz, (CD3OD) δ 7.99 (s, 1H), 7.70 (s, 1H), 7.62-7.50 (m, 3H), 7.50-7.47 (m, 3H), 7.37 (m, 1H), 5.20 (s, 1H), 4.40 (m, 2H), 4.07 (s, 3H), 3.85 (m, 2H), 2.55 (s, 3H), 2.34 (m, 2H), 0.94 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 100° C. and MS: m/e=305 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)(=[O:29])=[O:28])=[CH:22]2>>[F:40][C:37]([F:38])([F:39])[O:36][C:32]1[CH:31]=[C:30]([S:27]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]3[CH2:8]2)(=[O:28])=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(c1cccc(OC(F)(F)F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: CC(C)(C)OC(=O)N1CC2CN(c3cccc4cc(S(=O)(=O)c5cccc(OC(F)(F)F)c5)cnc34)CC2C1
Yield: 79 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 8-iodo-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline. 140 mg (79%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].C=O.[C:49]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[CH3:49][N:27]([CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1)C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.30 g) was suspended in methanol (3 ml). A 37% formaldehyde aqueous solution (0.11 g), sodium cyanoborohydride (89 mg) and acetic acid (1 ml) were added to the suspension and stirred at room temperature for 1 day. A 37% formaldehyde aqueous solution (0.22 g), sodium cyanoborohydride (178 mg) and acetic acid (2 ml) were further added to the mixture and stirred at room temperature for 1 day. The reaction mixture was gradually added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a pale brown powder (0.20 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C@@H:8]1[C:17]1[CH:22]=[CH:21][C:20]([CH:23](N2CCCC2)[CH3:24])=[CH:19][CH:18]=1>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C@@H:8]1[C:17]1[CH:18]=[CH:19][C:20]([CH:23]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH3:24])=[CH:21][CH:22]=1
Reactant: CC(c1ccc([C@H]2COc3ccccc3O2)cc1)N1CCCC1
Reactant: C1COCCN1
Product: CC(c1ccc([C@H]2COc3ccccc3O2)cc1)N1CCOCC1

Procedure:
Compound 226 is prepared from intermediate J and morpholine according to the procedure described for the synthesis of compound 225.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH2:10]SC)=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.[Ni]>[NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSCc1c(N)c(C#N)cc(F)c1F
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)c(C#N)cc(F)c1F
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol (80 ml) are added Raney nickel (40 ml) with ethanol (80 ml). The mixture is stirred at 40°-50° C. for 30 minutes, and then filtered. To the filtrate is added water, the reaction mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. The product is recrystallized from n-hexane to give 2-amino-4,5-difluoro-3-methylbenzonitrile (2.4 g), as a white crystal, m.p. 114°-116° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10](O)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:4]=[N:3]1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:10]1[C:11]2[CH:16]=[CH:15][NH:14][C:12]=2[N:13]=[C:8]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc(Nc2nc(O)c3cc[nH]c3n2)cn1
Product: Cn1cc(Nc2nc(Cl)c3cc[nH]c3n2)cn1
Yield: 56 %

Procedure:
A solution of 2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (5 g, 0.02 mol) in POCl3 (50 mL) was stirred at 120° C. for 4 hrs. After removal of POCl3 by rotary evaporation, water (37 mL) was added. The pH was adjusted to 10 by aq. NaOH (2 mol/L, 30 mL) and then extracted with EtOAc/THF (2:1, three×200 mL). The combined organic layers were concentrated to dryness to afford the title compound (2.8 g, 56% yield) as a brown solid, which was used as is in the next step.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([OH:19])=[O:18])[C:10]2=[O:15])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(NS(C)(=O)=O)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (85 mg, 0.240 mmol) and TFA (370 μl, 4.80 mmol) in 5 ml of DCM was stirred at room temperature overnight. The mixture was evaporated to obtain 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (72 mg, 0.240 mmol, 100% yield, MS/ESI+ 298.9 [MH]+) and used as such in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[C:13]([F:20])[C:12]=2[N:21]2[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>CN(C=O)C>[F:29][C:2]([F:1])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[C:13]([F:20])[C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CC[C@@H](F)C3)c(F)c21

Procedure:
The title compound is prepared in analogy to 1e from (R)—N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-fluoro-pyrrolidinyl]-3-fluoro-4-methylamino-5-amino-benzoic acid amide (215 mg, 0.51 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (162 mg, 0.51 mmol), DIC (80 μL) and DMF (4.0 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[O:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1ccc(-c2cccc3c2C(C)NCC3)o1
Product: Cc1ccc(-c2cccc3c2C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C.C(OCC)C>[CH2:17]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccnc2n1Cc1ccccc1
Temperature: 20 °C
Yield: 82 %

Procedure:
2 g (10 mmol) of ethyl pyrrolo[2,3-b]pyridine-2-carboxylate (WO2004101563) are added, portionwise, to a suspension of 0.44 g (11 mmol) of sodium hydride in 50 ml of DMF, stirred at 20° C. After stirring at ambient temperature for 1 h, 2.1 g (12 mmol) of benzyl bromide are added, dropwise, and the reaction mixture is stirred at ambient temperature for 20 h. 150 ml of water and 150 ml of ethyl ether are subsequently added with stirring. The aqueous phase is separated and extracted twice with 50 ml of ethyl ether. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of heptane and dichloromethane. 2.3 g of the expected product are thus isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:19])=O>CN(C)C=O>[CH3:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc(Nc2nc(C)c(C)c(O)n2)n1
Solvent: CN(C)C=O
Product: Cc1csc(Nc2nc(C)c(C)c(Cl)n2)n1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
The mixture solution of 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-hydroxypyrimidine (1.15 g, 4-78 mmol), phosphorus oxychioride(7 ml), and dimethylformamide(5 ml) was heated to 70° C. for 30 minutes, cooled to a room temperature and then poured into ice water. The aqueous layer was extracted with dichloromethane, washed with 1N sodium hydroxide solution, and then washed with water. The separated organic layer was concentrated and the residual oil was suspended in a mixture solution of ethyl ether and hexane. The resulting solid was filtered and dried to give 0.42 g of the titled compound. (Yield: 33.9%)
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:12][OH:13]>C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: Cc1cc2ncc(CO)c(N)n2n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2ncc(C=O)c(N)n2n1
Reaction time: 16 h

Procedure:
(7-amino-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (1-1) (14.1 g, 79.2 mmol) was dissolved in anhydrous CHCl3 (500 mL) and TI-IF (250 mL). Activated MnO2 (68.9 g, 792 mmol) was added to the mixture, and the mixture was stirred for 16 h. After filtration through a plug of Celite pad, the filtrate was evaporated to give 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1-2) as a yellowish solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](OC(C)(C)C)=O)[CH2:10]1.[OH-].[Na+].O>C1COCC1>[CH3:15][N:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([CH2:8][OH:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 106.4 %

Procedure:
A 2M solution of LiAlH4 in THF (14.0 mL, 28.0 mmol) was added drop-wise to a solution of (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (5.00 g, 23.2 mmol) in THF (30 mL) under argon at 0° C. The reaction mixture was allowed to warm to room temperature over 2 hours and stirred at room temperature for 17 hours. The reaction mixture was cooled to 0° C. and a 1M aq NaOH solution (4.0 mL) was added drop-wise. Water (2 mL) was added and the resulting mixture stirred at room temperature for 2 hours. The white solid was removed by filtration. The filtrate was concentrated in vacuo to give (R)-(1-methylpiperidin-3-yl)methanol (3.19 g, 106%) as a colourless oil which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:38])[C:10]2[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:9]1=2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:40]1[C:10]2[N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]5[CH:34]=[CH:35][CH:36]=[CH:37][C:28]4=5)=[O:26])=[CH:21][C:20]=3[CH3:38])[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH2:7][C:6]([OH:45])=[O:5])[C:9]=2[CH:43]=[CH:42][CH:41]=1
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)O)c2cccc(F)c21
Reaction time: 1.5 h

Procedure:
To a solution of {6-fluoro-5-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcabamoyl]-2-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]acetic acid tert-butyl ester from Example 1 (250 mg, 0.40 mmol) in dichloromethane (8 ml) was added trifluoroacetic acid (8 ml). The mixture was stirred for 90 min and evaporated in vacuo and azeotroped with toluene to give an off-white solid; yield 220 mg, 99%.